We've heard that elderly people and those with underlying health conditions are most at risk if they're infected with coronavirus, but those can seem like really general terms. Who does that include? And why can they face more serious illness?"According to the , some of the underlying conditions that may put you at higher risk include: chronic lung disease and asthma, heart disease and undergoing cancer treatment," said CNN Chief Medical Correspondent Dr. Sanjay Gupta. Anyone with diabetes, kidney failure or liver failure may also be at higher risk.The role of the immune system is to protect against disease or other potentially damaging pathogens. A strong one is needed to help stave off coronavirus infection."Think of it like this," Dr. Gupta suggested. "In your everyday life, you're always fighting off pathogens. Most of the time you don't even realize it. If you have an underlying condition, it makes it more challenging to fight off a virus like this. You may develop a fever, shortness of breath or a cough more easily than someone who doesn't have a preexisting illness."Additionally, there are more specific reasons why each condition has its own vulnerabilities. Here's a guide to underlying conditions affected by coronavirus and why, and how you can protect yourself or an at-risk loved one.Older adultsEight out of 10 deaths reported in the U.S. have been in adults ages 65 and older, according to the CDC. Older adults have also been more likely to require hospitalization and admission to an intensive care unit.Older adults are more likely to have long-term health problems that can increase their risk for infection and serious disease. And, our immune systems usually weaken with age, making it more difficult for people to fight off infections, according to Johns Hopkins Medicine.The quality of our lung tissue also declines over time, becoming more elastic and making respiratory diseases such as COVID-19 of important concern because of the potential for lung damage.Inflammation in older adults can be more intense, leading to organ damage.Those with lung disease, asthma or heart conditionsPeople with chronic airway and lung diseases such as chronic obstructive pulmonary disease, asthma, pulmonary fibrosis and interstitial lung disease can lay the foundations for more severe infection with coronavirus because of the inflammation, scarring and lung damage those conditions cause, Johns Hopkins Medicine reported.COVID-19 affects a person's airway and lungs, but those organs work together to provide the body with oxygen. When the lungs are overburdened with an infection, the heart has to work harder, which exacerbates the challenges of people already living with heart disease.The immunocompromisedAccording to the CDC, many conditions can cause a person to be immunocompromised, including cancer treatment, smoking, bone marrow or organ transplantation and immune deficiencies. Poorly controlled HIV or AIDS and prolonged use of man-made steroid hormones or other immune-weakening medications can also hamper a person's immune function.Cancer can weaken immunity by spreading into the bone marrow, which makes blood cells that help fight infection, according to Cancer Research UK. Cancer prevents bone marrow from making enough blood cells.Some cancer treatments can temporarily weaken the immune system, too. Because cancer treatments such as chemotherapy, cancer drugs, radiotherapy or steroids are targeted toward cancer cells, they can also diminish the number of white blood cells created in the bone marrow.A 2017 study found cigarette smoking can harm the immune system by either causing extreme immune responses to pathogens or rendering the body less effective at fighting disease. This may occur by smoking, negatively altering the cellular and molecular mechanisms responsible for keeping an immune system strong.When a person undergoes a bone marrow transplant using stem cells from a donor, or they receive an organ, a doctor may prescribe medications to prevent graft-versus-host disease and mitigate the immune system's reaction by suppressing its function. After the operation, it takes time for your immune system to be up and running again.HIV and AIDS attack the body's immune system, specifically the body's T cells, which help the immune system fight off infection. When the diseases are untreated, HIV reduces the number of those cells, making the person more likely to contract other infections or infection-related cancer, according to the CDC.Severe obesityPeople with severe obesity, or a body mass index of 40 or higher, are at higher risk of serious disease."Obesity shares with most chronic diseases the presence of an inflammatory component," a 2012 study said. Inflammatory responses were linked between the immune system and body fat. Obesity is known to impair immune function by altering white blood cell count as well as the cells that control immune responses.DiabetesPeople with type 1 or type 2 diabetes face an increased risk of getting really sick with COVID-19, as both cause a blood sugar spike. If blood sugar is poorly managed, viral diseases can be more dangerous as high blood sugar may give viruses a place to thrive, according to Diabetes in Control, a news and information resource for medical professionals.Higher levels of inflammation have been discovered in the bodies of people with diabetes, weakening the immune system and making it more difficult for those affected to stave off sickness in general.Kidney and liver diseaseThe kidneys produce several hormones that affect immune responses. Having kidney disease and failure can weaken your immune system, making it easier for infections to take hold. According to the National Kidney Foundation, doctors and researchers have found that most infections are worse in people with kidney disease.The liver is an integral member of the body's line of defense, helping to regulate the number of white blood cells utilized in immune responses and defend against harmful pathogens. Someone with liver disease is experiencing abnormalities in the function of the immune system, giving rise to more serious illness.Neurodevelopmental conditionsNeurological and neurodevelopmental conditions may also increase the risk of serious COVID-19 for people of any age.These include disorders of the brain, spinal cord, peripheral nerve and muscle such as cerebral palsy, epilepsy, stroke and intellectual disability, according to the CDC. Those with moderate to severe developmental delay, muscular dystrophy or spinal cord injury are also more at-risk.People with neurological conditions may not be more at risk due to solely their condition, but because medications they might take to control their condition could hamper their immune system. However, some neurological conditions, such as Parkinson's, have been recognized to have inflammatory components, which may harm the immune system.Others including muscular dystrophy, multiple sclerosis or amyotrophic lateral sclerosis (ALS) could cause paralysis to the diaphragm, which leaves those affected very at risk for respiratory failure if they were to be sick with COVID-19.Staying safe when you're more at riskIf you see yourself on the list of those at higher risk for severe illness, there are several things you can do to protect yourself. First, make sure you are contact your doctor or doctors about your risk level. Second, be extra vigilant about the recommendations that most people are being asked to follow.Stay home whenever possible and avoid close contact with people, the CDC suggests. Wash your hands often to prevent transferring the virus from a surface to your face, and try to clean and disinfect frequently touched surfaces as often as you can.If you don't have an underlying condition, doing your part by practicing these cautionary measures can help protect not only you, but your loved ones with existing conditions.

We've heard that elderly people and those with underlying health conditions are most at risk if they're infected with coronavirus, but those can seem like really general terms. Who does that include? And why can they face more serious illness?

"According to the [Centers for Disease Control and Prevention], some of the underlying conditions that may put you at higher risk include: chronic lung disease and asthma, heart disease and undergoing cancer treatment," said CNN Chief Medical Correspondent Dr. Sanjay Gupta. Anyone with diabetes, kidney failure or liver failure may also be at higher risk.

The role of the immune system is to protect against disease or other potentially damaging pathogens. A strong one is needed to help stave off coronavirus infection.

"Think of it like this," Dr. Gupta suggested. "In your everyday life, you're always fighting off pathogens. Most of the time you don't even realize it. If you have an underlying condition, it makes it more challenging to fight off a virus like this. You may develop a fever, shortness of breath or a cough more easily than someone who doesn't have a preexisting illness."

Additionally, there are more specific reasons why each condition has its own vulnerabilities. Here's a guide to underlying conditions affected by coronavirus and why, and how you can protect yourself or an at-risk loved one.

Eight out of 10 deaths reported in the U.S. have been in adults ages 65 and older, according to the CDC. Older adults have also been more likely to require hospitalization and admission to an intensive care unit.

Older adults are more likely to have long-term health problems that can increase their risk for infection and serious disease. And, our immune systems usually weaken with age, making it more difficult for people to fight off infections, according to Johns Hopkins Medicine.

The quality of our lung tissue also declines over time, becoming more elastic and making respiratory diseases such as COVID-19 of important concern because of the potential for lung damage.

Inflammation in older adults can be more intense, leading to organ damage.

People with chronic airway and lung diseases such as chronic obstructive pulmonary disease, asthma, pulmonary fibrosis and interstitial lung disease can lay the foundations for more severe infection with coronavirus because of the inflammation, scarring and lung damage those conditions cause, Johns Hopkins Medicine reported.

COVID-19 affects a person's airway and lungs, but those organs work together to provide the body with oxygen. When the lungs are overburdened with an infection, the heart has to work harder, which exacerbates the challenges of people already living with heart disease.

According to the CDC, many conditions can cause a person to be immunocompromised, including cancer treatment, smoking, bone marrow or organ transplantation and immune deficiencies. Poorly controlled HIV or AIDS and prolonged use of man-made steroid hormones or other immune-weakening medications can also hamper a person's immune function.

Cancer can weaken immunity by spreading into the bone marrow, which makes blood cells that help fight infection, according to Cancer Research UK. Cancer prevents bone marrow from making enough blood cells.

Some cancer treatments can temporarily weaken the immune system, too. Because cancer treatments such as chemotherapy, cancer drugs, radiotherapy or steroids are targeted toward cancer cells, they can also diminish the number of white blood cells created in the bone marrow.

A 2017 study found cigarette smoking can harm the immune system by either causing extreme immune responses to pathogens or rendering the body less effective at fighting disease. This may occur by smoking, negatively altering the cellular and molecular mechanisms responsible for keeping an immune system strong.

When a person undergoes a bone marrow transplant using stem cells from a donor, or they receive an organ, a doctor may prescribe medications to prevent graft-versus-host disease and mitigate the immune system's reaction by suppressing its function. After the operation, it takes time for your immune system to be up and running again.

HIV and AIDS attack the body's immune system, specifically the body's T cells, which help the immune system fight off infection. When the diseases are untreated, HIV reduces the number of those cells, making the person more likely to contract other infections or infection-related cancer, according to the CDC.

People with severe obesity, or a body mass index of 40 or higher, are at higher risk of serious disease.

"Obesity shares with most chronic diseases the presence of an inflammatory component," a 2012 study said. Inflammatory responses were linked between the immune system and body fat. Obesity is known to impair immune function by altering white blood cell count as well as the cells that control immune responses.

People with type 1 or type 2 diabetes face an increased risk of getting really sick with COVID-19, as both cause a blood sugar spike. If blood sugar is poorly managed, viral diseases can be more dangerous as high blood sugar may give viruses a place to thrive, according to Diabetes in Control, a news and information resource for medical professionals.

Higher levels of inflammation have been discovered in the bodies of people with diabetes, weakening the immune system and making it more difficult for those affected to stave off sickness in general.

The kidneys produce several hormones that affect immune responses. Having kidney disease and failure can weaken your immune system, making it easier for infections to take hold. According to the National Kidney Foundation, doctors and researchers have found that most infections are worse in people with kidney disease.

The liver is an integral member of the body's line of defense, helping to regulate the number of white blood cells utilized in immune responses and defend against harmful pathogens. Someone with liver disease is experiencing abnormalities in the function of the immune system, giving rise to more serious illness.

Neurological and neurodevelopmental conditions may also increase the risk of serious COVID-19 for people of any age.

These include disorders of the brain, spinal cord, peripheral nerve and muscle such as cerebral palsy, epilepsy, stroke and intellectual disability, according to the CDC. Those with moderate to severe developmental delay, muscular dystrophy or spinal cord injury are also more at-risk.

People with neurological conditions may not be more at risk due to solely their condition, but because medications they might take to control their condition could hamper their immune system. However, some neurological conditions, such as Parkinson's, have been recognized to have inflammatory components, which may harm the immune system.

Others including muscular dystrophy, multiple sclerosis or amyotrophic lateral sclerosis (ALS) could cause paralysis to the diaphragm, which leaves those affected very at risk for respiratory failure if they were to be sick with COVID-19.

If you see yourself on the list of those at higher risk for severe illness, there are several things you can do to protect yourself. First, make sure you are contact your doctor or doctors about your risk level. Second, be extra vigilant about the recommendations that most people are being asked to follow.

Stay home whenever possible and avoid close contact with people, the CDC suggests. Wash your hands often to prevent transferring the virus from a surface to your face, and try to clean and disinfect frequently touched surfaces as often as you can.

If you don't have an underlying condition, doing your part by practicing these cautionary measures can help protect not only you, but your loved ones with existing conditions.

Read more:
What are the underlying conditions causing more serious illness from coronavirus? - WPBF West Palm Beach

Spinal Cord Stem Cells Comments Off on What are the underlying conditions causing more serious illness from coronavirus? – WPBF West Palm Beach | April 17th, 2020

Abstract

The skin constantly renews itself throughout adult life, and the hair follicle undergoes a perpetual cycle of growth and degeneration. Stem cells (SCs) residing in the epidermis and hair follicle ensure the maintenance of adult skin homeostasis and hair regeneration, but they also participate in the repair of the epidermis after injuries. We summarize here the current knowledge of epidermal SCs of the adult skin. We discuss their fundamental characteristics, the methods recently designed to isolate these cells, the genes preferentially expressed in the multipotent SC niche, and the signaling pathways involved in SC niche formation, SC maintenance, and activation. Finally, we speculate on how the deregulation of these pathways may lead to cancer formation.

Keywords: hair follicle, multipotency, self-renewal, cell fate determination, Wnt signaling, Bmp, cancer

Skin and its appendages ensure a number of critical functions necessary for animal survival. Skin protects animals from water loss, temperature change, radiation, trauma, and infections, and it allows animals to perceive their environment through tactile sense. Through camouflage, the skin provides protection against predators, and it also serves as decoration for social and reproductive behavior.

Adult skin is composed of a diverse organized array of cells emanating from different embryonic origins. In mammals, shortly after gastrulation, the neurectoderm cells that remain at the embryo surface become the epidermis, which begins as a single layer of unspecified progenitor cells. During development, this layer of cells forms a stratified epidermis (sometimes called interfollicular epidermis), the hair follicles (HRs), sebaceous glands, and, in nonhaired skin, the apocrine (sweat) glands. Mesoderm-derived cells contribute to the collagen-secreting fibroblasts of the underlying dermis, the dermovasculature that supplies nutrients to skin, arrector pili muscles that attach to each hair follicle (HF), the subcutaneous fat cells, and the immune cells that infiltrate and reside in the skin. Neural crestderived cells contribute to melanocytes, sensory nerve endings of the skin, and the dermis of the head. Overall, approximately 20 different cell types reside within the skin.

In the adult, many different types of stem cells (SCs) function to replenish these various cell types in skin as it undergoes normal homeostasis or wound repair. Some SCs (e.g., those that replenish lymphocytes) reside elsewhere in the body. Others (e.g., melanoblasts and epidermal SCs) reside within the skin itself. This review concentrates primarily on epidermal SCs, which possess two essential features common to all SCs: They are able to self-renew for extended periods of time, and they differentiate into multiple lineages derived from their tissue origin (Weissman et al. 2001).

Mature epidermis is a stratified squamous epithelium whose outermost layer is the skin surface. Only the innermost (basal) layer is mitotically active. The basal layer produces, secretes, and assembles an extracellular matrix (ECM), which constitutes much of the underlying basement membrane that separates the epidermis from the dermis. The most prominent basal ECM is laminin5, which utilizes 31-integrin for its assembly. As cells leave the basal layer and move outward toward the skin surface, they withdraw from the cell cycle, switch off integrin and laminin expression, and execute a terminal differentiation program. In the early stages of producing spinous and granular layers, the program remains transcriptionally active. However, it culminates in the production of dead flattened cells of the cornified layer (squames) that are sloughed from the skin surface, continually being replaced by inner cells moving outward ().

Epidermal development and hair follicle morphogenesis. The surface of the early embryo is covered by a single layer of ectodermal cells that adheres to an underlying basement membrane of extracellular matrix. As development proceeds, the epidermis progressively stratifies and acquires layers of terminally differentiating cells that are required to establish a functional barrier. During embryonic development, some of the undifferentiated basal cells are instructed by the underlying dermis (signal 1) to adopt a hair follicular fate. Subsequently, the epidermis sends a message to the dermis (signal 2) to make the dermal papilla (DP). Finally, the DP sends a message to the developing follicle (signal 3), allowing its growth and differentiation to form the discrete lineages of the hair follicle and its hair. Encased by a basement membrane, the basal layer of the follicle is referred to as the outer root sheath (ORS). At the base of the mature follicle is the highly proliferative compartment called the matrix (Mx). Matrix cells differentiate to form the concentric rings of differentiating cells that give rise to the hair shaft, its channel (the inner root sheath, IRS), and the companion layer. Hair follicles also contain sebaceous glands to ensure the water impermeability of the hair and lubricate the hair channel and skin surface.

The major structural proteins of the epidermis are keratins, which assemble as obligate heterodimers into a network of 10-nm keratin intermediate filaments (IFs) that connect to 64-integrin-containing hemidesmosomes that anchor the base of the epidermis to the laminin5-rich, assembled ECM. Keratin IFs also connect to intercellular junctions called desmosomes, composed of a core of desmosomal cadherins. Together, these connections to keratin IFs provide an extensive mechanical framework to the epithelium (reviewed in Omary et al. 2004). The basal layer is typified by the expression of keratins K5 and K14 (also K15 in the embryo), whereas the intermediate suprabasal (spinous) layers express K1 and K10. Desmosomes connected to K1/K10 IFs are especially abundant in suprabasal cells, whereas basal cells possess a less robust network of desmosomes and K5/K14. Rather, basal cells utilize a more dynamic cytoskeletal network of microtubules and actin filaments that interface through -and -catenins to E-cadherin-mediated cell-cell (adherens) junctions, in addition to the 1-integrin-mediated cell-ECM junctions (reviewed in Green et al. 2005, Perez-Moreno et al. 2003). Filaggrin and loricrin are produced in the granular layer. The cornified envelope seals the epidermal squames and provides the barrier that keeps microbes out and essential fluids in (Candi et al. 2005, Fuchs 1995) (). The program of terminal differentiation in the epidermis is governed by a number of transcription factor families, including AP2, AP1, C/EBPs, Klfs, PPARs, and Notch (reviewed in Dai & Segre 2004).

Although the molecular mechanisms underlying the process of epidermal stratification are still unfolding, several studies have recently provided clues as to how this might happen. Increasing evidence suggests the transcription factor p63 might be involved. Mice null for the gene encoding p63 present an early block in the program of epidermal stratification (Mills et al. 1999, Yang et al. 1999).

There are several possible mechanisms by which stratification could be achieved with an inner layer of mitotically active cells and suprabasal differentiating layers. In the first mechanism, a proliferating basal cell progressively weakens its attachment to the basement membrane and to its neighbors and is pushed off the basal layer and up into the spinous layer. In vitro studies demonstrated that this process, referred to as delamination, effectively allows stratification (Vaezi et al. 2002, Watt & Green 1982). A possible alternative to delamination is that basal cells in a stratifying tissue might orient their mitotic plane of division perpendicular to the underlying basement membrane, which would consequently place one of the two daughter cells in the suprabasal layer.

Recent studies in mice suggest that during embryonic development in skin, the majority of mitotic cells within the epidermis go from having their spindle plane parallel to the basement membrane to a perpendicular orientation (Lechler & Fuchs 2005, Smart 1970). In these perpendicular orientations, the apical centriole associates with a complex containing Nuclear Mitotic Apparatus protein, partitioning-defective protein 3, atypical protein kinase C, Inscuteable, and partner of inscuteable. The association with this cortical complex is intriguing because most of these evolutionarily conserved proteins have been shown genetically to be essential for the asymmetric cell divisions that occur in Drosophila neuroblasts and in Caenorhabditis elegans embryos (Cowan & Hyman 2004, Wodarz 2005). Although many features of the underlying mechanism remain to be addressed, proper spindle orientation appears to require 1-integrin and -catenin, further underscoring the importance of basement membrane and adherens junctions in the establishment of epidermal polarity and tissue architecture (Lechler & Fuchs 2005). More studies are now needed to determine the respective role of asymmetrical cell division and delamination during development, skin homeostasis, and pathological conditions such as wound healing.

The development of HFs involves a temporal series of epithelial-mesenchymal interactions (reviewed in Hardy 1992) (). First, the dermis signals to the overlying epidermis to make an appendage. In response, the epidermis then transmits a signal to instruct the underlying dermal cells to condense and form the dermal papilla (DP). Another signal is then sent from the DP to promote the proliferation and elaborate differentiation required to form the epidermal appendage.

The process of HF development has been divided into discrete stages distinguished by their morphological and biochemical differences (Paus et al. 1999). The first morphological sign of HF development is the formation of a hair placode, in which the basal epithelium becomes elongated and invaginates at sites where dermal condensates form. As the developing follicle extends downward and en-wraps the DP, the cells at the base maintain a highly proliferative state. During follicle maturation, these proliferating (matrix) cells begin to differentiate into the inner root sheath (IRS), which is the envelope for the future hair shaft and is marked by the expression of the transcription factor GATA3 and the structural protein trichohyalin (Kaufman et al. 2003, O'Guin et al. 1992). The outer layer of cells becomes the outer root sheath (ORS), which is contiguous with the epidermis and is surrounded externally by the basement membrane. The ORS expresses K5 and K14, similar to the interfollicular epidermis. As the follicle continues to widen, a new inner core of cells appears and begins to express the hair keratin genes of the hair shaft (reviewed in Omary et al. 2004). By postnatal day 8 in mice, follicle downgrowth is complete, and for the next 7 days, matrix cells proliferate and differentiate into the six concentric layers of the IRS and hair shaft ().

At postnatal day 16, proliferation in the matrix ceases, and the lower two-thirds of the HF rapidly degenerates by a process involving apoptosis (catagen stage). An epithelial strand surrounded by the retracting basement membrane draws the DP upward, where in backskin it comes to rest just below the base of this permanent segment of the HF called the bulge. This resting stage is referred to as telogen. In the first hair cycle, telogen lasts approximately one day, but in subsequent cycles, this phase becomes increasingly extended, suggesting the need to reach a biochemical threshold before the next hair cycle can be activated. The new cycle of hair regeneration (anagen) begins with the emergence of a proliferating hair germ, and the progression to form the mature follicle bears a significant resemblance to embryonic folliculogenesis (Muller-Rover et al. 2001) (). The periodic cycling of hair growth and degeneration persists throughout the life of the animal and implicates the existence of SCs to fuel the regenerative process.

The hair follicle cycle. When matrix cells exhaust their proliferative capacity or the stimulus required for it, hair growth stops. At this time, the follicle enters a destructive phase (catagen), leading to the degeneration of the lower two-thirds of the follicle. The upper third of the follicle remains intact as a pocket of cells surrounding the old hair shaft (club hair). The base of this pocket is known as the bulge, which is the natural reservoir of hair follicle stem cells (SCs) necessary to form a new hair follicle. After catagen, the bulge cells enter a quiescent stage (telogen), in which the DP is now in close contact with bulge SCs. In the mouse, the first telogen lasts approximately one day, after which all the hair follicles synchronously enter a new cycle of regeneration and hair growth (anagen stage). The bulge as a structure develops when the new hair must emerge from the original orifice, which is often shared by the old club hair. Subsequent hair cycles involve increasingly longer telogen phases, resulting in considerably less synchronous hair cycles.

The molecular mechanisms that govern HF morphogenesis and cycling are still poorly understood, but genetic studies in mice reveal the importance of Wnt/-catenin, bone morphogenetic protein (Bmp), sonic hedgehog (Shh), fibroblast growth factor (Fgf), epidermal growth factor receptor (Egf), NFkB, and Notch signaling pathways (reviewed in Millar 2002, Schmidt-Ullrich & Paus 2005).

The adult skin epithelium is composed of molecular building blocks, each of which consists of a pilosebaceous unit (HF and sebaceous gland) and its surrounding interfollicular epidermis (IFE). The IFE contains its own progenitor cells to ensure tissue renewal in the absence of injury, and HFs contain multipotent SCs that are activated at the start of a new hair cycle and upon wounding to provide cells for HF regeneration and repair of the epidermis.

The IFE, which generates the lipid barrier of adult skin, constantly renews its surface throughout the entire life of the animal and also undergoes reepithelialization after wound injuries. These renewing and repairing activities of the skin epidermis imply the existence of SCs to ensure these critical functions. Histological analysis has shown that mouse epidermis is organized in stacks of cells with a hexagonal surface area lying on a bed of ten basal cells (Mackenzie 1970; Potten 1974, 1981). This structure was hypothesized to function as an epidermal proliferative unit (EPU) with one putative SC per unit. Researchers tested experimentally the existence of EPUs using lineage-tracing analyses. The first type of lineage tracing was performed by infecting cultured mouse and human keratinocytes with a retrovirus expressing LacZ and grafting these marked keratinocytes onto immunodeficient mice. Alternatively, mice were directly infected with LacZ-virus in skin, following dermabrasion (Ghazizadeh & Taichman 2001, Kolodka et al. 1998, Mackenzie 1997). Analysis of the chimeric skin revealed the presence of discrete columns of blue cells from the basal cells to the most differentiated uppermost layer of cells. These findings demonstrate that EPUs exist in the basal IFE and can be maintained individually as a separate unit for extended periods of time. Such domains can be explained by a mechanism whereby basal cells divide asymmetrically relative to the basement membrane to maintain a proliferative daughter and give rise to a differentiating daughter cell overlying it (Lechler & Fuchs 2005).

Self-renewal within the epidermis has also been studied using genetic fate mapping, which circumvents the wound response generated in transplantation experiments (Ro & Rannala 2004). In this case, transgenic mice were engineered to express a mutant form of green fluorescent protein (GFP) that cannot be translated owing to the presence of a stop codon in the EGFP-coding sequence. Subsequently, the mice received topical application of a mutagen to induce mutations that can remove the stop codon and restore expression of a functional GFP protein. These sporadic mutations resulted in patches of GFP-positive cells within the IFE, allowing the visualization of EPU columns. Although elegant, these experiments did not address how many SCs are present in each EPU and where the SCs reside within the unit.

In human skin, the epidermis is thicker and undulates to form deep epidermal ridges (rete ridges) that extend downward in the epidermis and help to anchor the epidermis to the dermis. Used only sparingly, SCs have been proposed to cycle less frequently. The infrequently cycling cells within the IFE are located at the base of these ridges, which is conveniently in a more protected site than elsewhere within the IFE (Lavker & Sun 1982).

To identify characteristics of IFE SCs, researchers have turned toward in vitro experiments. Cultured human IFE keratinocytes expressing the highest level of 1-integrin have the highest proliferative potential in vitro (Jones & Watt 1993). Other genes have also been shown to be preferentially expressed in 1-enriched human keratinocytes, underscoring the biochemical distinctions of this population of basal cells (Legg et al. 2003). As would be expected, the 1-bright cells are found in the basal layer, but interestingly, they reside in clusters (Jones et al. 1995). Additionally, the 1-bright cells do seem to reside at the base of the deepest epidermal ridges of palmoplantar skin, consistent with the location of slow-cycling SCs observed by Lavker & Sun (1982). Elsewhere, however, the 1-bright clusters reside outside these zones, in a seemingly more compromised position for SCs. Hence, the extent to which 1-integrin levels define the distinguishing features of IFE SCs must await further studies. In this effort, additional markers are needed to enrich the purification and analyses of IFE cells with high proliferative potential. Such markers should also help in defining the location and the number of IFE SCs within their functional EPU columns and in discerning the extent to which less frequent cycling is a measure of stemness within the IFE population. A final issue to be resolved is the extent to which cells with high proliferative potential in the basal layer of the IFE are able to contribute to other cell lineages, i.e., those of the sebaceous gland and HF.

In the mid-1970s, Rheinwald & Green (1975) defined culture conditions allowing the growth of human IFE SCs in vitro. This seminal discovery allowed the propagation of keratinocytes from severely burned patients and their subsequent grafting as sheets of autologous cultured cells that were functional in reepithelializing the damaged skin (Gallico et al. 1984, O'Connor et al. 1981, Pellegrini et al. 1999, Ronfard et al. 2000). In the past 25 years, this technology has saved many lives. Although the patient's repaired skin epithelium does not regenerate sweat glands or HFs, it does have a normal epidermis, which can undergo wound repair.

When plated at low cell density, cultured human keratinocytes can form three types of colonies: (a) highly proliferative colonies (holoclones) of small round cells that present an undifferentiated morphology and that can be passaged long-term, (b) aborted colonies (paraclones) displaying large flat morphology typical of terminally differentiated cells, and (c) relatively small heterogeneous colonies (meroclones) of limited proliferative potential that become senescent after a few rounds of passaging (Barrandon & Green 1987). Although the term holoclone refers only to the proliferative capacity of the colony, the progeny of a single epidermal holoclone in vitro can re-form a functional and renewable epidermis in vivo (Rochat et al. 1994). This implies that at least some cells within holoclones possess the fundamental characteristics of a SC in that they can self-renew and differentiate into a functional tissue. By contrast, meroclones have been likened to so-called transit-amplifying cells, i.e., cells with a limited number of cell divisions before they commit to terminally differentiate. Although the precise physiological relevance of these cultured populations of cells remains to be determined, the in vitro description of their clonal properties has served as a useful foundation for the analyses of SCs in vivo.

In the hair follicle, SCs reside in a discrete microenvironment called the bulge, located at the base of the part of the follicle that is established during morphogenesis but does not degenerate during the hair cycle. Bulge SCs are more quiescent than other cells within the follicle. However, during the hair cycle, bulge SCs are stimulated to exit the SC niche, proliferate, and differentiate to form the various cell types of mature HFs. In addition, to provide cells during HF regeneration, the bulge SC is a reservoir of multipotent SCs that can be recruited during wound healing to help the repair of the epidermis. We summarize here the recent progress in the functional and molecular characterization of bulge SCs.

For many years, it was thought that the SCs that regenerate HFs during the hair cycle are the highly proliferative matrix cells (Kligman 1959). This model was later challenged when Montagna & Chase (1956) observed that X-ray irradiation kills the matrix cells, but hairs can still re-form from cells within the ORS. The ability of the upper ORS to act in concert with the DP to make HFs was further substantiated by dissection and transplantation experiments (Jahoda et al. 1984; Oliver 1966, 1967).

Mathematical modeling has supported the notion that SCs may be used sparingly and hence divide less frequently than their progeny (Potten et al. 1982). This notion was bolstered by administering repeated doses of marked nucleotide analogs such as BrdU or 3[H]-thymidine to label the S-phase cycling cells of the skin (pulse period) and then following the fate of the incorporated label over time (chase period). The differentiating cells are sloughed from the skin surface, and the more proliferative cells dilute their label as they divide, marking the least proliferative cells as label-retaining cells (LRCs) (Bickenbach 1981).

To locate HF LRCs, Lavker and colleagues (Cotsarelis et al. 1990) administrated BrdU for a week in newborn mice and then analyzed label retention in the skin after four weeks of chase. The majority of LRCs in the skin resided in a specialized region at the base of the permanent segment of the HF. Known as the bulge, this region was described more than a century ago by histologists (Stohr 1903). Within the ORS, the bulge resides just below the sebaceous gland at a site where the arrector pili muscle attaches to the follicle (). Although its origins are likely to be traced to the early stages of HF embryogenesis, the bulge acquires its distinctive appearance when the first postnatal hair germ emerges before the prior club hair has been shed (). During the first telogen phase, a single layer of quiescent cells surround the old club hair; as the new hair cycle initiates, the bulge acquires a second layer of cells (Blanpain et al. 2004).

Although generally quiescent, bulge cells can be prompted to proliferate artificially in response to mitogenic stimuli such as phorbol esters (TPA) or naturally at the start of each hair cycle. In an elegant double-label study to demonstrate a precursor-product relation, Taylor et al. (2000) showed that when BrdU-labeled LRCs in the bulge are exposed to a brief pulse of a second nucleotide label, they incorporate 3[H]-thymidine as they exit and proliferate to develop the new hair germ. To directly determine whether the bulge region contains SCs, Barrandon and coworkers (Kobayashi et al. 1993) dissected rat and human HFs and assessed the growth potential of different HF segments in vitro. In rat-whisker follicles, 95% of the derived holoclones came from cells of the bulge segments, whereas less than 5% of the growing colonies could be derived from the matrix region. In adult human skin, keratinocytes with high proliferative potential were also found within bulge segments, but the zone of clonogenic cells was broader, extending from the bulge to the lower ORS (Rochat et al. 1994). In this regard, in adult human skin, the bulge is notably a less distinctive structure than it is in rodents.

Early studies involving reepithelialization during wound repair led researchers to posit that HFs may have the capacity to regenerate epidermis upon injury (Argyris 1976). To evaluate whether bulge LRCs have this capacity, Taylor et al. (2000) extended their double-labeling techniques to wound-healing experiments. Indeed, following a wound, BrdU-labeled cells derived from the bulge could be found proliferating within the epidermis near the HF orifice (infundibulum).

Fuchs and coworkers (Tumbar et al. 2004) recently adapted the nucleotide pulse-chase experiments to the protein level by engineering mice expressing a tetracycline-regulated histone H2B-GFP protein in their skin epithelium. In the absence of tetracycline, all the skin epithelial nuclei were green with H2B-GFP expression, but when tetracycline was administered, the gene was shut off, and after four weeks, only the bulge cells still labeled brightly with H2B-GFP protein (). Upon wounding, H2B-GFP-positive cells were detected in the epidermis and infundibulum, confirming the ability of bulge LRCs to reepithelialize the epidermis in response to injury (Tumbar et al. 2004). Upon activation of the hair cycle, the emerging hair germ displayed H2B-GFP-positive cells with much weaker fluorescence than the bulge, suggesting that they were derived from the bulge LRCs. These findings support the studies of Barrandon, demonstrating the ability of bulge cells to regenerate the HF during the normal hair cycle.

The bulge stem cells (SCs). Bulge (Bu) SCs are more quiescent than are other keratinocytes with proliferative potential in the skin. Tumbar et al. (2004) developed a strategy for conducting fluorescent pulse-chase experiments in mice engineered to express a tetracycline-regulatable H2B-GFP transgene. After labeling all the skin epithelial cells with H2B-GFP, a four-week chase resulted in significant H2B-GFP-label retention only in the bulge (a). Label-retaining cells (LRCs) could be found along the basal layer of cells that express 64-integrins, as well as in a suprabasal location within the bulge (b). Bulge SCs express a high level of the cell surface protein CD34, which has been used with 6-integrin to isolate basal and suprabasal bulge cells, using flow cytometry (Blanpain et al. 2004, Trempus et al. 2003). [The approximate fluorescence of the outer root sheath (ORS) and interfollicular epidermis (IFE) cells is also indicated on the FACS profile.] Tissues were counterstained with Dapi (blue) to mark the nuclei. Abbreviations used: Cb, club hair; HF, hair follicle; SG, sebaceous gland.

Several lines of evidence suggest that there is a continuous flux of bulge cells throughout the growing stage of the hair cycle. During the anagen phase of the backskin hair cycle, Tumbar et al. (2004) detected a trail of H2B-GFP-positive cells along the lower ORS. Although these cells were less bright than their bulge LRC counterparts, the results were intriguing in light of rat-whisker bulge transplantation and clonogenic experiments performed by Barrandon and colleagues (Oshima et al. 2001). Based on these seminal studies, researchers proposed that SCs migrate from the bulge along the basal layer of the ORS to the matrix, where they proliferate and differentiate to produce the hair and IRS. Although the hair cycle of whisker follicles differs from those in the backskin in that the growing stage is longer and follicles transit from mid-catagen directly to anagen, a common theme for SC movement and activation likely applies for HFs, irrespective of whether they are whisker or pelage follicles.

In the past ten years, researchers have made considerable strides in isolating and purifying cells from the HF bulge. Given the complexity of the skin, purification of bulge cells using flow cytometry (FACS) has focused on isolating bulge cells in the simpler, telogen-phase follicles, where the quiescent bulge marks the base. Kaur and colleagues (Li et al. 1998) have employed conjugated antibodies against 6-integrin and anti-CD71 (antitransferin Ab or 10G7) to show that 6-bright, CD71-dim cells from skin possess similar colony-forming efficiency but higher long-term growth potential than the rest of the population. Bulge LRCs share this expression pattern and are enriched in the 6-bright, CD71-dim population by approximately twofold (Tani et al. 2000). Other markers such as S100A4 and S100A6 proteins (Ito & Kizawa 2001), K19 (Michel et al. 1996), K15 (Lyle et al. 1998), and CD34 (Trempus et al. 2003) have also been reported to exhibit preferential expression in the bulge. Although most of these antibodies have not proven useful for isolating living bulge cells by FACS, CD34 is an exception. CD34-positive cells are enriched tenfold for LRCs, and they form larger colonies than unfractionated epidermis (Trempus et al. 2003).

When transgenic expression of a basal epidermal marker (K14-GFP) is used in conjunction with antibodies against 6-integrin and CD34, purification of bulge cells is enhanced substantially (Blanpain et al. 2004). On the basis of differential 6 expression, the CD34/K14-GFP-positive cells from the inner and outer layers of the mature bulge can also be fractionated (). Bulge cells have also been purified from K15-GFP-transgenic skin in conjunction with 6-integrin antibodies (Morris et al. 2004), and when tetracycline-regulatable H2B-GFP mice are employed for bulge purification, a 70-fold enrichment of bulge LRCs can be achieved over unfractionated skin epithelial cells (Tumbar et al. 2004). In all three of these methods for obtaining bulge cells with high purity, bulge cells form large colonies that can be passaged in vitro (Morris et al. 2004, Tumbar et al. 2004). This is true for both the inner and the outer layer of the bulge (Blanpain et al. 2004) (). Clonogenicity studies further demonstrate that a large colony derived from a single bulge cell can give rise to multiple large colonies upon passaging, implying the occurrence of SC self-renewal in vitro (Blanpain et al. 2004, Claudinot et al. 2005).

The two major properties of SCs are their abilities to self-renew and to differentiate along multiple lineages. To address the differentiation potential of bulge SCs, researchers have used a variety of methods, including (a) transplantation studies of microdissected HF segments, (b) direct transplantation and clonal analysis of isolated bulge cells, and (c) genetic fate mapping in mice.

In pioneering studies, Oshima et al. (2001) generated chimeric rodent-whisker follicles by removing the unlabeled bulge of a wild-type vibrissae follicle, replacing it with a lacZ-expressing bulge microdissected from a transgenic mouse-whisker follicle and transplanting the chimeric follicle into the kidney capsule and/or embryonic backskin from immunodeficient mice. Thirty days after transplantation, lacZ-marked cells were detected in the epidermis, sebaceous gland, and HFs (Oshima et al. 2001). Morris et al. (2004) have obtained similar results using 105-FACS-isolated K15-GFP-tagged bulge cells transplanted into immunodeficient mice.

In the experiments of Barrandon and coworkers, temporal analysis of anagen-phase chimeric whisker follicles revealed a downward flux of lacZ-positive cells originating from the transplanted bulge, migrating to the matrix and subsequently differentiating into one of the six concentric rings of IRS and hair shaft lineages. Although at reduced frequency, cells residing in the lower HF were also able to differentiate into multiple skin cell lineages (Oshima et al. 2001). These findings support the view that SCs migrate from the bulge to the base of the follicle before they differentiate and lose their potential. As outlined above, it still remains to be resolved as to whether a continuous downward flux of bulge cells occurs only in whiskers or human HFs, in which the hair cycle displays a prolonged anagen phase, or whether it is a feature common to all HFs.

The studies above beautifully underscore the potential of cells within the bulge region to differentiate along the three different lineages afforded to the skin keratinocyte. However, they do not address whether the bulge consists of multiple types of unipotent progenitors, each of which are able to differentiate along one lineage, or whether individual bulge cells possess multipotency, the ability to differentiate along any of the three lineages. To date, technical hurdles have precluded testing for multipotency using in vivo clonal analyses. However, in the past few years, researchers have employed clonal analyses in vitro to demonstrate definitively the multipotency of bulge cells when passaged in vitro (Blanpain et al. 2004, Claudinot et al. 2005).

In the first study, Fuchs and coworkers (Blanpain et al. 2004) placed isolated K14-GFP-tagged bulge cells in culture to obtain individual holoclones. After short-term expansion, the descendents from a single bulge cell were then transplanted onto the backs of nude mice. The progeny of single bulgederived holoclones each gave rise to GFP-positive HFs, IFE, sebaceous gland, and even bulge SCs (Blanpain et al. 2004). Similar results were obtained by Barrandon and coworkers (Claudinot et al. 2005), who were able to generate thousands of HFs from the progeny of a single cultivated rat-whisker SC. These experiments provide compelling evidence in support of the notion that cells within the adult follicle bulge possessing the classical criteria of bona fide multipotent SCs. That the inner bulge layer also has this capacity further suggests that even when bulge cells detach from the basal lamina and appear to undergo early commitment to the HF lineage, the process is reversible, at least after in vitro culture (Blanpain et al. 2004).

Under normal circumstances, the bulge acts as a reservoir of follicle SCs, and only in response to injury has it been shown to mobilize and function as a multipotent SC reservoir. Whether there are other multipotent SCs in adult skin remains to be demonstrated. However, there is substantial evidence that unipotent SCs exist in other locations in the skin. Fate-mapping experiments using a Cre recombinase that permanently marks bulge cells reveal that under physiological conditions, the IFE contains only rare patches of -galactosidase-positive cells derived from bulge cells. These data reinforce the notion postulated above on the basis of EPU columns: Normal IFE homeostasis is controlled by the presence of unipotent progenitors that reside within the IFE (Ito et al. 2005, Levy et al. 2005, Morris et al. 2004). That bulge SCs are not necessary for epidermal homeostasis is perhaps best exemplified by the fact that palmoplantar skin lacks HFs altogether, as do a number of genetic hair disorders, yet epidermal homeostasis and wound repair can still take place (Montagna et al. 1954).

To determine which genes and signaling pathways operate within the bulge SCs, researchers have performed transcriptional profiling on isolated telogen-phase bulge cells (Blanpain et al. 2004, Morris et al. 2004, Tumbar et al. 2004). In most cases, these profiles have been compared with those of basal epidermal cells, which have proliferative capacity but are thought to contain few if any multipotent SCs. Notably, most of the transcripts upregulated in either the Tumbar or Morris arrays were upregulated in the Blanpain array, which encompassed a considerably larger gene set compared with the two earlier studies. Blanpain et al. (2004) list 56 transcripts that scored as upregulated in bulge cells irrespective of the isolation method, hair cycle stage, or attachment to the basal lamina and that can be viewed as a molecular signature of bulge cells.

Interestingly, 14% of genes found to be upregulated in other types of SCs (hematopoeitic SC, neuronal SC, and embryonic SC) (Ivanova et al. 2002, Ramalho-Santos et al. 2002) were also found to be a part of the bulge signature (Blanpain et al. 2004), suggesting that certain genes within this list are likely involved in the unique properties common to many if not all SCs. Related to this issue are the important similarities recently uncovered between these mouse bulge SC profiles and those of human bulge SCs (Ohyama et al. 2006). Although some differences were noted (CD34, for example, extends to the lower ORS in human follicles), this similarity bodes well for future clinical studies aimed at improving the potential of skin SCs for therapeutic purposes.

The bulge signature now provides a constellation of markers that should enable researchers to examine the extent to which bulge cells retain their program of gene expression as they respond to natural stimuli, e.g., during the hair cycle and upon injury, and as they exit the niche to migrate and/or differentiate along particular lineages. The list should also be useful in examining how the bulge cells change their properties in response to various genetic manipulations. Through such future examinations, scientists should begin to uncover the extent to which the bulge signature is a reflection of the quiescence of these SCs and identify the subset of these genes involved in self-renewal and in suppression of lineage determination irrespective of whether a skin SC is quiescent or proliferative.

Although these studies are in their infancy, a few important lessons are already emerging. One intriguing aspect of the transcriptional profiling conducted on the bulge to date is the high degree to which the bulge signature is maintained in both anagen and telogen stages of the hair cycle and in basal and suprabasal bulge layers (Blanpain et al. 2004). These findings underscore the powerful influence that the microenvironment of the bulge niche has on its residents. In turn, for a bulge SC to become mobilized and exit the niche, this dominance must be overcome.

Although researchers are conducting additional experiments to dissect the molecular significance of the bulge signature, it is tempting to speculate on the roles of various transcripts that are either up- or downregulated preferentially in the bulge. To this end, a number of bulge signature genes encode cell adhesion, cytoskeleton, and ECM components. We posit that these genes may reflect the specialized microenvironment that must be suitable not only for maintaining their SC characteristics within the niche, but also for allowing bulge SCs to exit their niche and migrate during wound repair and/or in hair regrowth.

The bulge signature also provides a battery of candidate genes likely to play a role in SC quiescence. Most notable are the many upregulated genes encoding cell-cycle inhibitory factors, such as Cdkn1b (p27), Cdkn1c (p57), and Cdkn2b (p15), and the numerous downregulated genes encoding cell-cycle-promoting factors, such as Ki67, proliferating cell nuclear antigen, cyclins (Cyclin D1, D2, A2, B1) and cyclin-dependent kinases, and cell-division-cycle-related genes (Cdc2a, 2b, 6, 7, 25c) (Blanpain et al. 2004, Morris et al. 2004, Tumbar et al. 2004). Although the cell cycle is typically thought to be regulated largely at the posttranslational level, the transcriptional regulation of these cell-cycle genes suggests that the quiescent nature of the bulge is governed by unique operational control mechanisms.

Finally, another interesting set of bulge signature genes contains those that are likely involved in maintaining the SCs in an undifferentiated, growth-inhibited state. Of these genes, it is particularly interesting that many components of the Wnt/-catenin signaling pathway (Tcf3; Tcf4; Dkk-3; sFRP1; Fzd 2, 3, 7; Dab2; Ctbp2) and the TGF-/Bmp signaling pathways (Ltbp1, 2, 3; Tgf-2; Gremlin) are upregulated in the bulge. These pathways are discussed individually in the sections below.

The Wnt/-catenin signaling pathway is conserved throughout the eukaryotic kingdom, where it controls a myriad of different cellular decisions during embryonic and postnatal development (). Wnt deregulation leads to an imbalance of proliferation and differentiation, often resulting in cancers (Reya et al. 2001).

The Wnt/-catenin signaling pathway during hair follicle (HF) morphogenesis and regeneration. (a) Schematic of the canonical Wnt pathway (for more details, see http://www.stanford.edu/%7Ernusse/). In the absence of a Wnt signal, the excess of cytoplasmic -catenin is targeted for degradation through its association with a multiprotein complex. Upon binding Wnt, its activated receptor complex recruits certain key components of the -catenin degradation targeting machinery. Stabilized free cytoplasmic -catenin is now translocated to the nucleus, where it can associate with transcription factors of the LEF/TCF family to transactivate the expression of their target genes. (b) Loss- and gain-of-function studies in mice have highlighted the different functions of Wnt/-catenin signaling during morphogenesis and adult skin homeostasis. During HF morphogenesis, Wnt/-catenin is required to specify the HF (placode) fate in the undifferentiated basal epidermis. During the adult hair cycle, Wnt/-catenin is required to maintain HF stem cell (SC) identity. As judged by a Wnt reporter transgene, an increase in Wnt signaling promotes SC activation to initiate the growth of a new hair during the telogen-to-anagen transition. An even stronger signal appears to be involved later at the transition of matrix cells to commit to terminally differentiate specifically along the hair shaft lineage. (c) When a constitutively active form of -catenin is expressed for sustained periods in skin epidermis, mice develop de novo HFs from the interfollicular epidermis (IFE), outer root sheath (ORS), and sebaceous glands (SGs). Eventually, these mice develop HF tumors called pilomatricoma, which consist of immortalized matrix-like cells at the periphery, and pure hair cells in the centers (no inner root sheath or companion layer cells). Visualization was enhanced by breeding the K14-N mice on a background of K14-GFP mice. (d) The different signal strengths of Wnt reporter gene activity, combined with the -catenin dosage dependency associated with these different outcomes in mice, can be explained by a model whereby the effective strength of Wnt signaling controls the behavior and fate of the follicle SC. Note: The so-called gradient of Wnt activity refers to the status of Tcf/Lef/-catenin transcriptional activity within the cell, which in fact could be achieved as a gradient, without even involving a Wnt per se. DP, dermal papilla.

Wnts compose a large family of cysteine-rich secreted glycoproteins that activate Frizzled receptors, which in turn stimulate a cascade of events culminating in the stabilization and accumulation of cytoplasmic -catenin. Normally, cellular -catenin is complexed with E-cadherin and -catenin at adherens junctions, and free cytoplasmic -catenin is degraded by the proteasome. Upon Wnt signaling, excess -catenin is no longer degraded, and it is free to complex with and activate members of the Tcf/Lef1 family of transcription factors (Logan & Nusse 2004) ().

The sonic hedgehog (Shh) signaling pathway during hair follicle morphogenesis and adult hair cycle. (a) Schematic of the Shh pathway. In the absence of Shh, its receptor Patched (Ptch) inhibits Smoothened (Smo) activity. Upon Shh binding, Ptch can no longer repress Smo, which activates the translocation of Gli into the nucleus, allowing it to transactivate its target genes. (b) The role of Shh in the hair follicle. Loss-of-function studies in mice have revealed the importance of Shh in sustaining proliferation in the embryonic and adult hair germ. Gain-of-function studies underscore the striking relation between basal cell carcinomas and deregulation of the Shh pathway. (c) Shh is not expressed in the quiescent bulge stem cells. During hair regeneration, there is a lag before Shh is strongly activated in the developing hair germ. Sustained expression of Shh seems to rely on close association with the dermal papilla (DP). Both in embryonic development and the adult, Shh appears to act downstream of the Wnt/-catenin signaling pathway. Bu, bulge; HG, hair germ.

In the skin, Wnt and -catenin play diverse roles in HF morphogenesis, SC maintenance and/or activation, hair shaft differentiation, and also pilomatricoma tumor formation in mice and humans (Alonso & Fuchs 2003). Activation of Wnt/-catenin signaling is critical during the first stage of HF morphogenesis, as evidenced by the absence of placode formation on conditional ablation of -catenin (Huelsken et al. 2001) or constitutive expression of a soluble Wnt inhibitor (Dkk1) (Andl et al. 2002). Although the source and identity of the putative Wnt signal required to induce placode formation remain elusive, it may be the first dermal signal to instruct epidermal cells to make hair. Consistent with this notion is the activation in both the placode and the postnatal hair germ of a Wnt reporter gene driving lacZ under the control of an enhancer composed of multimerized binding sites for the Lef1/Tcf DNA-binding proteins that interact with and are activated by association with -catenin (DasGupta & Fuchs 1999, Reya & Clevers 2005) (). Nuclear -catenin and Lef1 expression are also seen in embryonic placodes and postnatal hair germs at this time (Merrill et al. 2004, van Genderen et al. 1994, Zhou et al. 1995). Noggin, a soluble inhibitor of Bmps, is expressed by the mesenchymal condensate and is required in the early stage of HF morphogenesis and cycling. It appears to act at least in part by promoting expression of Lef1 (Botchkarev et al. 2001, Jamora et al. 2003).

Transgenic mouse studies support a role for Wnt signaling in the specification of HF development. Mice expressing a constitutively stabilized -catenin (>N-catenin) display de novo HFs (Gat et al. 1998) (), whereas mice lacking Lef1 (van Genderen et al. 1994) or -catenin (Huelsken et al. 2001) or overexpressing the Wnt inhibitor Dkk1 exhibit a paucity of follicles (Andl et al. 2002).

Postnatally, the strongest Wnt signal is associated with the terminally differentiating cortical cells of the hair shaft (DasGupta & Fuchs 1999) (). The hair keratin genes possess Lef1/Tcf DNA-binding domains and are bona fide targets for Wnt-mediated gene expression (Merrill et al. 2001, Zhou et al. 1995). This lineage of the matrix cells appears to be particularly singled out for robust Wnt signaling, as K14-N-catenin transgenic mice develop pilomatricomas, which are pure tumor masses of cortical cells (Gat et al. 1998). Similarly, the majority of human pilomatricomas possess N-terminal stabilizing mutations in the coding sequence of the -catenin gene (Chan et al. 1999, Xia et al. 2006).

In contrast to the cortical cells, the bulge is largely silent for Wnt reporter activity (DasGupta & Fuchs 1999). Microarray data suggest that the bulge is normally in a Wnt-inhibited environment, showing an upregulation of genes encoding putative Wnt-inhibitory factors (sFRP1, Dkk3, Wif) and a downregulation of genes encoding Wnt-promoting factors in the bulge (Wnt3, Wnt3a). However, bulge SCs express a number of frizzled surface receptors (Fz2, 3, and 7) to enable them to receive Wnt signals as well as Wnt-signaling-related transcription factors (Tcf3, Tcf4, Tle1, Ctbp2) to enable them to transmit a Wnt signal (see Tumbar et al. 2004). In this regard, Tcf3 is intriguing, as it has been shown to act as a repressor in the absence of Wnt signaling (Merrill et al. 2001, 2004). Taken together, these findings suggest that bulge SCs are in a quiescent, Wnt-inhibited state and that Wnt signaling plays a key role in driving these cells along at least one hair differentiation lineage ().

Several studies suggest that the role of Wnt signaling in the postnatal HF may be even broader. The involvement of Wnts in HF morphogenesis suggests that Wnt signaling may be important for activating bulge SCs. Consistent with this notion is the presence of a few Wnt-reporter-driven, LacZ-positive bulge cells at the beginning of the hair cycle (DasGupta & Fuchs 1999). The number of activated bulge cells can be considerably enhanced by breeding the Wnt-reporter mice on the background of K14-N-catenin mice; at most stages of the hair cycle, however, the bulge remains silent for Wnt-reporter activity (DasGupta & Fuchs 1999, Merrill et al. 2001).

By inducing the expression of stabilized -catenin in telogen-phase follicles, several groups have observed precocious activation of hair regeneration (Lo Celso et al. 2004, Lowry et al. 2005, Van Mater et al. 2003), in a fashion reminiscent of the de novo follicle morphogenesis that occurs in the IFE (Gat et al. 1998). Despite the premature transition from telogen to anagen, the K14-N-catenin bulge reenters its relatively quiescent state once the follicle has grown downward (Lowry et al. 2005). These findings imply that some additional factor(s) is required in addition to elevated Wnt signaling to change the status of Lef1/Tcf-regulated genes (including TopGal) and activate bulge SCs. It is tempting to speculate that this signal emanates from the DP, given the close proximity of the DP to the bulge prior to the start of the hair cycle. One candidate may be the Bmp-inhibitor Noggin, produced by the DP and shown to be required for Lef1 expression in the embryonic hair placode and in the matrix cells as well (Andl et al. 2004, Botchkarev et al. 1999, Jamora et al. 2003, Kobielak et al. 2003). Fgf7 and Fgf10 are additional candidates known to be expressed in the bulge and to have an impact on follicle morphogenesis (Guo et al. 1993, Petiot et al. 2003).

Despite the continuous presence of an elevated level of stabilized -catenin, the size of the SC niche does not change over time (Lowry et al. 2005). This means that if elevated -catenin promote the self-renewal of bulge SCs, it must be accompanied by an increase in the rate at which SCs exit the niche. Two factors consistent with this notion are that the rate of BrdU-label retention is reduced and the level of BrdU-label incorporation is enhanced in the K14-N-catenin bulge. That said, this increased proliferation appears to be manifested in precocious SC activation, as it was not accompanied by a noticeable increase in the length of the hair or the cellularity of HFs.

To understand how -catenin elevation can promote SC activation in the bulge, Lowry et al. (2005) conducted microarray analyses on telogen- or anagen-phase SCs isolated from N-catenin or wild-type follicles. Intriguingly, some telogen-phase bulge genes affected by N-catenin were similarly affected in the normal anagen-phase bulge, suggesting the transgene-induced changes may reflect natural changes that occur in the telogen-to-anagen transition of the hair cycle. Although further studies are needed to assess the extent to which this is the case, genes that surfaced in these arrays and that may play a role in Wnt-mediated bulge SC activation include Cyclin D2 (Ccnd2), Sox4, and Biglycan (Lowry et al. 2005). Another protein upregulated in the early anagen bulge appears to be the transcriptional corepressor Hairless, which has been proposed to function by blocking the expression of the soluble Wnt inhibitor Wise, which in turn may lead to Wnt-mediated SC activation (Beaudoin et al. 2005). An additional interesting twist is the recent study reporting that Shh is a downstream target of Wnt-mediated activation of follicle SCs (Silva-Vargas et al. 2005). Shh is particularly intriguing as a Wnt candidate, as it would integrate these two key signaling pathways essential for HF morphogenesis. That said, on the basis of the differential expression of direct Wnt target genes and Shh, it seems unlikely that Shh is a direct target for Wnt signaling in bulge cells (Lowry et al. 2005). We discuss the Shh pathway in greater depth below.

In summary, these findings delineate sequential roles for Wnt signaling in temporally regulating follicle SC lineages, perhaps in a fashion that depends on the level of the signal: (a) -catenin stabilization promotes bulge SC activation, proliferation, and induction of follicle regeneration; (b) -catenin stabilization promotes the specification of matrix cells to terminally differentiate along the hair (cortical) cell lineage; (c) -catenin stabilization promotes de novo HF morphogenesis; and (d) constitutively active -catenin expression results in pilomatricoma hair tumors. The particular fate selected by a follicle cell appears to depend on a constellation of intrinsic and extrinsic factors, which together influence the status of Tcf/Lef1-regulated genes. At the Wnt-inhibited end of the spectrum is SC quiescence, and at the constitutive Wnt end is tumorigenesis ().

Similar to Wnt/-catenin, Shh is an ancient signaling pathway involved in cell fate specification and proliferation during animal development (Taipale & Beachy 2001). The Shh transmembrane receptor is Patched (Ptch), which is active in the absence of Shh (). Ptch functions by inhibiting Smoothened (Smo), which is essential to transduce the Shh signal through the Gli family of transcription factors to induce target gene expression. Ptch itself is a Shh target gene, resulting in the localized sequestration of Shh and the restriction of long-range signaling (Casali & Struhl 2004).

Given the prominence of the Shh pathway in development and proliferation, it is not surprising to find that when deregulated, this pathway leads to tumorigenesis. Rubin et al. (2005) illuminated its importance in skin with the finding that Ptch1 gene mutations cause basal cell nevus syndrome, a hereditary predisposition to basal cell carcinomas (BCCs), the most common type of skin cancer in humans. In the skin, Ptch acts as a tumor suppressor gene, as loss of heterozygosity at the Ptch locus (chromosome 9q22.3) has been observed in sporadic BCC and BCCs isolated from patients with basal cell nevus syndrome (Gailani et al. 1996, Hahn et al. 1996, Johnson et al. 1996, Unden et al. 1996). Activating mutations in Smo have also been detected in sporadic BCCs (Xie et al. 1998), and overexpression of Shh, Smo, Gli1, or Gli2 leads to BCCs in mice (Dahmane et al. 1997, Grachtchouk et al. 2000, 2003; Hutchin et al. 2005; Oro et al. 1997; Xie et al. 1998). Recently, Vidal et al. (2005) demonstrated that an HMG transcription box factor, Sox9, is also upregulated in BCC, and epistasis experiments suggest that Sox9 is downstream of the Shh signaling pathway in skin.

BCCs are thought to be derived from HFs, and consistent with this notion, Shh is expressed in the hair placodes of embryonic skin (St-Jacques et al. 1998) (). As revealed by Ptch expression, Shh is likely to signal in both the epithelial hair germ and its underlying mesenchymal condensate, suggesting its potential role in the epithelial-mesenchymal cross talk essential for follicle formation (Oro & Higgins 2003, Oro et al. 1997). Loss-of-function mutations in Shh are still permissive for hair germ formation, placing Shh genetically downstream of Wnt and Noggin signaling (). However, placodes fail to develop further, thus positioning Shh upstream from the proliferative cascade essential for HF morphogenesis (Chiang et al. 1999, St-Jacques et al. 1998, Wang et al. 2000). Mice deficient in Gli2 present a phenotype similar to Shh-null mice, suggesting that Shh acts mainly through Gli2 in HF (Mill et al. 2003).

Shh signaling is also important for follicle regeneration during the adult hair cycle. Although not expressed in the bulge, Shh is expressed in the matrix and in the developing germ, where it becomes polarized to one side during anagen progression (). The mechanisms underlying this exquisite restriction in expression are not understood, but Shh signaling is likely to span the matrix, as evidenced by Ptch expression (Gat et al. 1998, Oro & Higgins 2003). As would be predicted from the relative roles of Shh and Wnt signaling in embryonic skin, anti-Shh antibodies delivered to postnatal follicles block anagen progression (Wang et al. 2000), and similarly the Shh inhibitor cyclopamine blocks hair regeneration (Silva-Vargas et al. 2005). Conversely, Shh or small-molecule Shh agonists accelerate the progression from telogen to anagen (Paladini et al. 2005, Sato et al. 1999).

Whereas Shh plays a role in matrix cell proliferation in the hair cycle, Indian hedgehog (Ihh) is expressed in the sebaceous gland. Additionally, both human and mouse sebaceous tumors overexpress Ihh but not Shh. In normal sebaceous glands, Ihh is expressed in differentiating sebocytes, and nuclear Gli1 is present in sebocyte progenitors (Niemann et al. 2003). In vitro inhibition of hedgehog signaling inhibits growth and stimulates differentiation of sebocytes, suggesting a paracrine mechanism by which Ihh secreted by differentiated sebocytes stimulates proliferation of sebocyte precursors (Niemann et al. 2003). Transgenic overexpression of the other members of Shh family shows that Desert hedgehog is a functional homolog to Shh in the skin (Adolphe et al. 2004).

Bmps are secreted proteins that activate signal transduction by binding to a transmembrane receptor complex composed of Bmpr1a and Bmpr1b receptors. Upon ligand binding, Bmpr1b phosphorylates the cytoplasmic tail of Bmpr1a, which in turns phosphorylates the R-Smad DNA-binding protein (Smad 1, 5, and 8), which in turn complexes with one of its partner Smads (typically Smad 4) to translocate to the nucleus and mediate target gene expression (Shi & Massague 2003) ().

Bone morphogenetic protein (BMP) signaling pathway during hair follicle morphogenesis and differentiation. (a) Schematic of the BMP pathway. The extracellular availability of BMP proteins is tightly regulated by soluble BMP inhibitors such as Noggin. BMP dimers bind a heterodimeric receptor complex (BMPR-I and BMPR-II) that phosphorylates and activates R-Smad (Smads 1, 5, and 8), which then associates with its co-Smad (Smad 4) partner. Once activated, the R-Smad/co-Smad complex is translocated into the nucleus, where it transactivates its target genes. (b) Role of BMPs in hair follicle morphogenesis. BMP signals are transmitted to and from the overlying epidermis to underlying dermal condensates. Although the role these BMP signals play is not fully understood, this exchange of signaling is thought to play a role in the early specification of sites of hair follicle morphogenesis. As dermal condensates form, they express the BMP-inhibitor Noggin, which is required for normal follicle development and permissive for Lef1 expression and Wnt signaling. Later, as follicle maturation has progressed, the activation of BMP receptor signaling is essential for the matrix cells to differentiate to form the hair shaft and its inner root sheath (IRS) channel. BMP signaling also regulates epidermal proliferation in the skin. DP, dermal papilla.

Bmpr1a is expressed throughout most of the developing skin epithelium. The pattern of Bmp expression is particularly elaborate in the HF. In early skin development, Bmp2 is expressed in the placode epithelium, whereas Bmp4 is expressed by the underlying mesenchyme (Kratochwil et al. 1996; Lyons et al. 1989, 1990; Wilson et al. 1999). In adult HFs, Bmps also appear to function in epithelial-mesenchymal interactions. In the DP, Bmp4, -6, and -7 are expressed (Kratochwil et al. 1996; Lyons et al. 1989, 1990; Rendl et al. 2005; Wilson et al. 1999), although Bmp6 may also function in bulge SC quiescence and/or maintenance (Blanpain et al. 2004). In addition, Bmps are differentially expressed in the various lineages of the HF, with Bmp7 and -8 in the IRS and Bmp2 and -4 in the hair shaft precursors.

The role for Bmp signaling in skin development begins in the neuroepithelium, when Bmp signaling specifies uncommitted ectodermal cells to become epidermis (Nikaido et al. 1999). Once the embryonic skin SC progenitor cells have been specified, the next crossroads for signaling appears to be at the juncture of hair placode formation. In a process bearing a certain resemblance to the formation of the neural tube, placode formation is dependent on Noggin, a soluble inhibitor of Bmp signaling (Botchkarev et al. 1999, Jamora et al. 2003). Conditional ablation of the Bmpr1a gene also results in the accumulation of large masses of undifferentiated, Lef1-expressing, placode-like cells, further emphasizing a role for Bmp inhibition in the early stages of HF morphogenesis (Andl et al. 2004, Kobielak et al. 2003).

The conditional targeting of the Bmpr1a gene also revealed a positive role for Bmp signaling in the differentiation of matrix cells into IRS and hair shaft lineages (Andl et al. 2004, Kobielak et al. 2003, Ming Kwan et al. 2004, Yuhki et al. 2004). Several markers of matrix cell differentiation (FoxN1/nude, Hoxc13, Msx2, and GATA3) were strongly reduced or absent following the ablation of Bmpr1a. Notably and in striking contrast, Shh and Lef1 expression was expanded, as is also seen in transgenic mice expressing Noggin under the control of the Msx2 promoter (Kulessa et al. 2000). Nuclear -catenin was also decreased in the Bmpr1a-deficient matrix cells, demonstrating that Bmp signaling lies upstream of -catenin signaling during matrix cell differentiation. These findings strengthen the view that the inhibition of Bmp signaling is required for SC activation toward the HF cell fate, whereas Bmp signaling is required for the differentiation of activated SCs to adopt one or more of the six different lineages that compose the mature HF (Kobielak et al. 2003).

Several other lines of evidence suggest that the inhibition of Bmp signaling promotes SC activation. At the conclusion of the normal hair cycle, proliferation ceases and the HF enters the destructive phase (catagen). By contrast, Bmpr1a-null ORS continues to proliferate and grow downward, leading to an accumulation of matrix cells and the formation of follicular tumors (Andl et al. 2004, Ming Kwan et al. 2004). Conversely, treatment of cultivated bulge SCs with BMP6 inhibits their proliferation and leads to a transient withdrawal from the cell cycle (Blanpain et al. 2004, Botchkarev et al. 1999).

Similar to other major signaling pathways in skin, Notch signaling is involved in a variety of cell fate decisions across the animal kingdom. Transmembrane Notch receptors (Notch14 in mammals) bind transmembrane ligands, either Jaggeds (2) or deltas (3). Upon ligand engagement, membrane Notch receptors are sequentially cleaved, first by a metalloproteinase and then by -secretase, which releases the active Notch intracellular domain (NICD), freeing it to translocate to the nucleus and associate with the DNA-binding protein RBP-J. Upon NICD binding, RBP-J is converted from a transcriptional repressor to an activator, leading to the induction of downstream Notch target genes (Artavanis-Tsakonas et al. 1999) ().

Notch signaling pathway during epidermal stratification and hair follicle differentiation. (a) Schematic of canonical Notch signaling. Upon ligand (Jagged or Delta) binding, the Notch transmembrane receptor is cleaved by proteases (ADAM protease and -secretase), releasing the Notch intracellular domain (NICD), which can then translocate into the nucleus and associate with the DNA-binding protein RBP-Jk to permit transcription of target genes. (b) Role of Notch1 in skin development. Notch1 is cleaved and generates its active form, NICD1, which controls epidermal stratification and differentiation. Early, NICD1 is present in basal cells but later it is found primarily in suprabasal cells. Loss-of-function studies suggest that Notch1 acts as a tumor suppressor in skin epidermis to restrict proliferation to the basal layer. Notch1 also plays a role in the hair follicle, where it has been demonstrated to play a critical role in the differentiation of the inner root sheath and the hair shaft.

Multiple components of the Notch signaling pathway are expressed in embryonic and adult epidermis. During the early stage of epidermal stratification, Notch1 is expressed and active in the basal and suprabasal cells of the epidermis and sebaceous glands (Okuyama et al. 2004, Rangarajan et al. 2001) (). In the latter stages of epidermal stratification, Notch1 activity decreases in the basal layer and becomes more restricted to the spinous layer (K1-positive cells) (Okuyama et al. 2004). Loss of Notch1 function results in a defect of IFE differentiation (Rangarajan et al. 2001).

In the HF, Notch13 are expressed in proliferative matrix cells and in differentiating HF cells (Kopan & Weintraub 1993, Pan et al. 2004) (). When both Notch 1 and Notch2 or PS1 and PS2 genes involved in Notch processing are conditionally ablated in the matrix, HFs are quantitatively lost and epidermal cysts arise, underscoring the role for Notch signaling in follicle maturation and differentiation (Pan et al. 2004). The consequences of Notch1 deletion are most directly deleterious to the sebaceous glands, which are reduced in the single conditional knockout animals; in the absence of both Notch1 and Notch2, sebaceous glands are missing altogether (Pan et al. 2004). Conditional gene targeting of RBP-J also results in hair loss and epidermal cyst formation (Yamamoto et al. 2003).

Related to the natural role of Notch signaling in skin, loss of Notch 1 potentiates skin tumor development upon chemically induced carcinogenesis (Nicolas et al. 2003). Conversely, NICD overexpression in cultured cells inhibits keratinocyte proliferation, in part by upregulating the p21 target gene, which possesses a functional RBP-J-binding site within its promoter (Rangarajan et al. 2001). Although these studies point to a role for Notch in hair differentiation and inhibition of proliferation, sustained activation of Notch signaling through NICD1 overexpression in hair shaft progenitors unexpectedly promotes matrix cell proliferation and impairs hair shaft differentiation (Lin & Kopan 2003, Lin et al. 2000). These findings raise the possibility that the roles for Notch signaling in the epidermis and HF may be distinct.

Further insights into Notch signaling in the skin come from studies on chicken feather formation. As in mice, Notch1 is expressed in chick epidermal placode, and delta is expressed in the underlying mesenchyme. Delta overexpression in a small epidermal patch leads to an acceleration of feather development, whereas massive overexpression in the epidermis leads to a decrease in feather development (Crowe et al. 1998). These findings suggest a model in which Notch signaling promotes HF development in the preexisting placode but restricts neighboring cells from adopting a similar fate. The generalization of this model for other appendage development in other species requires further investigation, but the model mirrors that of Notch signaling in epidermal and neural fate specification in Drosophila.

Although loss of Notch1 in the epidermis does not impair early follicle morphogenesis, it does progressively reduce the number of HFs over time (Vauclair et al. 2005). It is still unclear what the downstream genes regulated by Notch signaling in the epidermis are, and how these genes mediate their cellular function. It also remains to be determined how Notch signaling acts in the bulge SC niche, how Notch regulates hair cycle, and how the Notch signaling pathway is connected to the other signaling pathways known to influence SC maintenance and activation.

The ends of chromosomes are called telomeres, and they consist of short, tandem DNA sequence repeats that associate with specific proteins and protect chromosome ends from degradation and recombination. Telomerase is a reverse transcriptase that synthesizes the DNA repeats to circumvent telomere shortening during DNA replication. Telomerase reverse transcriptase (TERT) is the catalytic subunit of the protein complex that makes the telomerase. Telomerase is upregulated in many human cancers, and TERT cooperates with other oncogenes to transform normal cells into tumor cells (Blackburn 2001).

TERT has been postulated to extend the proliferative potential of cells, and hence it has been speculated to play a role in SC biology. When the K5 promoter is used to drive TERT overexpression in the basal epidermal layer of transgenic mice, animals are more susceptible to skin tumorigenesis when exposed to chemical carcinogens, and they repair their wounds more rapidly (Gonzalez-Suarez et al. 2001). Conversely, mice deficient for TERC, another key component of telomerase, are resistant to skin chemical carcinogenesis (Gonzalez-Suarez et al. 2000).

In bulge SCs, increased TERT activity results in proliferation and premature entry into the anagen stage (Flores et al. 2005, Sarin et al. 2005). Flores et al. (2005) assumed that the reduced epidermal proliferation seen in TERC-null mice reflected the importance of telomerase and telomere length in bulge SC behavior. In contrast, Sarin et al. (2005) discovered surprisingly that TERC affects the skin in a fashion independent of its role in telomerase function and telomere length. Both groups have posited that TERT and TERC exert their function on the quiescent SCs within the bulge. However, given the need to sustain proliferation in the matrix cells during the growth phase of the hair cycle, it seems more plausible that a need for enhancing conventional telomerase activity would be felt by the proliferating matrix compartment rather than the infrequently cycling cells of the bulge. Additional studies are needed to clarify these conflicting results and determine the mechanism by which telomerase overexpression allows or facilitates skin carcinogenesis and SC activation.

Bulge SCs display elevated levels of several cytoskeleton-related genes known to be regulated by small G proteins of the Rho family of small GTPases. Rac is a pleiotropic regulator of actin dynamics, intercellular adhesion, and cell migration, and as such, it is expressed broadly in proliferating cells. Conditional ablation of the Rac1 gene in the proliferating keratinocytes of skin rapidly depletes the proliferative compartments, leading to a mobilization and depletion of SCs (Benitah et al. 2005).

A priori, a similar outcome might be expected for the depletion of many different types of essential epidermal genes. However, Rac1 was of particular intrigue to Watt and her colleagues (Arnold & Watt 2001, Braun et al. 2003, Frye et al. 2003, Waikel et al. 2001) because it is a negative regulator of c-Myc, whose elevated expression has been reported to deplete the population of bulge LRCs. It will be interesting in the future to see the extent to which, as posited by the authors, Rac1 may act at the nexus of the transition between the SC and its committed progeny (Benitah et al. 2005).

Given the general consensus that overexpression of c-Myc depletes bulge SCs and drives them to differentiate along the epidermal lineage (Arnold & Watt 2001, Braun et al. 2003, Frye et al. 2003, Waikel et al. 2001), it came as a surprise that conditional loss of endogenous c-Myc also leads to a loss of bulge LRCs and precocious differentiation of basal epidermal cells (Zanet et al. 2005). Although the jury is still out, one possible explanation for the seemingly disparate results between gain and loss of c-Myc function is that c-Myc acts at multiple points along the bulge SC lineages, and a perturbation at one or more of these steps may indirectly impact the behavior of SCs. Consistent with this notion is that both gain- and loss-of-function studies point to a role for c-Myc in governing the sebaceous gland lineage, which is also thought to rely on bulge SCs.

The skin epithelium is a complex tissue containing three distinct lineages that form the IFE, the HF, and the sebaceous gland.

The IFE constantly self-renews to provide a new protective layer at the skin surface, and HFs undergo a perpetual cycle of growth and degeneration to ensure the renewal of the hair pelage.

Different populations of progenitor cells contribute to lineage homeostasis, but to date, only bulge SCs have been demonstrated clonally to be multipotent with the ability to differentiate into all three differentiation lineages.

Bulge SCs can be activated and mobilized, at each cycle of hair follicle regeneration and after wound healing, to provide cells for tissue repair.

Recent progress in the isolation and molecular characterization of bulge SCs has provided new insights into the various mechanisms implicated in SC maintenance and activation.

Conserved signaling pathways regulating developmental decisions throughout the animal kingdom are reutilized during adult life to regulate the functions of skin epithelial SCs, and deregulation of these signaling pathways leads to the development of cancer in various tissues.

In this review, we try to highlight some of the significant advances made recently in skin stem cell biology, and we place them within the context of the historical foundations that made this current research possible. In closing, we offer a few of the unanswered questions in the field of skin stem cells that we think are likely to capture the attention of skin biologists in the years to come.

Do common molecular mechanisms govern the fundamental characteristics shared by adult skin SCs and other SCs, namely self-renewal and maintenance of the undifferentiated state? Comparisons of the transcriptional profiles of different types of SCs isolated directly from their respective tissues should help to identify possible candidates, as will the profiling of SCs residing in and out of their niches, and in quiescent and activated states. As candidate genes are identified, functional analyses of putative self-renewal or differentiation inhibitory SC genes in skin should reveal their importance and begin to unravel the pathways involved.

What is the mechanism by which quiescent bulge SCs are activated? Little is known about the signals needed to mobilize bulge SCs to reepithelialize epidermal wounds and to replenish the sebaceous gland. Even for the better understood process of SC activation during the hair cycle, a number of key issues remain unsolved. At the crux of the problem is whether follicle SC activation involves an intrinsic clock mechanism and/or whether it involves a signal from the DP. Although a change in the status of Lef1/Tcf/-catenin-regulated genes has been implicated in follicle SC activation, it is still not clear where a Wnt signal is involved, where it comes from, how the pathway exerts its effects, how it converges with other key signaling pathways, and how the program of gene expression is established that leads to follicle formation.

What is the relationship between the bulge SCs and the proliferative compartments of the epidermis, sebaceous gland, and HF? Do proliferating skin keratinocytes retain unipotent or even multipotent SC properties, or are they committed to embark on a terminal differentiation program? The point of no return in the skin SC field is an important one. Lineage-tracing experiments and the recent studies on asymmetric cell divisions in the skin provide new insights into these issues, but additional studies are now needed to illuminate the molecular relations between these different proliferative populations within the skin.

What is the relationship between the multipotent progenitors of embryonic skin epidermis and the multipotent SCs of the bulge? Embryonic skin effectively begins as a single layer of multipotent progenitors, but they differ from bulge SCs in their proliferative status and their lack of an apparent niche. Are bulge SCs simple quiescent counterparts of their embryonic brethren, or are there intrinsic differences between them? As methods are honed to isolate and characterize the early embryonic SCs, this relationship should become clearer. Additionally, it will be helpful to trace the development of the bulge from its early origins to its site in the postnatal follicle.

Are SCs at the root of cancers in the skin? Cancer is the result of a multistep process requiring the accumulation of mutations in several genes. For most cancers, the target cells of oncogenic mutations are unknown. Adult SCs may be the initial target cells, as they self-renew for extended periods of time, providing increased opportunity to accumulate the mutations required for cancer formation. Certain cancers contain cells with SC characteristics with high self-renewal capacities and the ability to re-form the parental tumor on transplantation. However, whether the initial oncogenic mutations arise in normal SCs or in more differentiated cells that reacquire SC-like properties remains to be determined. The demonstrations that SCs are the target cells of the initial transforming events and that cancers contain cells with SC characteristics await the development of tools allowing for the isolation and characterization of normal adult SCs. For most epithelia in which cancer arises, such isolation techniques are not available. The new methods to isolate and specifically mark skin SCs make it now possible to test experimentally the cancer SC hypothesis in the skin.

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Epidermal Stem Cells of the Skin - PubMed Central (PMC)

Skin Stem Cells Comments Off on Epidermal Stem Cells of the Skin – PubMed Central (PMC) | April 16th, 2020

Medical skin care products are used for beautifying or to address some other skin care problems. The cosmetic industry is booming and skin care forms a very huge part of this industry. The aesthetic appearance is so important that people spend a lot on skin care products and treatment. People being more technologically aware of the various new skin care products trending in the market. In addition to the aesthetic application, the medical skin care products are also used to address issues such as acne, pimples or scars.

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Medical Skin Care Products Market: Drivers and Restraints

The medical skin care products is primarily driven by the need of natural based active ingredients products which are now trending in the market. Consumers demand medical skin care products which favor health and environment. Moreover, the consumers are updated with the trends so that various companies end up providing such products to satisfy the customers. For instance, a single product face mask has thousands of different variants. This offers consumers different options to select the product depending on the skin type. Moreover, the market players catering to the medical skin care products are offering products with advanced technologies. For instance, Santinov launched the CICABEL mask using stem cell material based on advanced technologies. The stem cells used in the skin care product helps to to protect and activate the cells and promote the proliferation of skin epidermal cells and the anagenesis of skin fibrosis.

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On the basis of product type the medical skin care products market can be segmented as:

On the basis of application, the medical skin care products market can be segment as:

On the basis of distribution channel, the medical skin care products market can be segment as:

Medical Skin Care Products Market: Overview

Medical skin care products are used to address basic skin problems ranging from acne to scars. There are various advancements in the ingredients used to offer skin care products to the consumers. For instance, the use of hyaluronic acid and retinoids is the latest development in the industry. The anti-aging creams are at the forefront as the help treating issues such as wrinkles, scars, acne, and sun damage. Another, product in demand is the probiotic skincare which include lactobacillus and bifidobacterium.

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Medical Skin Care Products Market: Region-wise Outlook

In terms of geography, medical skin care products market has been divided into five regions including North- America, Asia- Pacific, Middle-East & Africa, Latin America and Europe. North America dominated the global medical skin care products market as international players are acquiring domestic companies to make their hold strong in the U.S. LOral is accelerating its U.S. market by signing a definitive agreement with Valeant Pharmaceuticals International Inc. to acquire CeraVe, AcneFree and Ambi skin-care brands for US$ 1.3 billion. The acquisition is expected LOreal to get hold of the brands in the price-accessible segment. Asia Pacific is expected to be the fastest growing region owing to the increasing disposable income and rising awareness towards the skin care products.

Medical Skin Care Products Market: Key Market Participants

Some of the medical skin care products market participants are ,

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Medical Skin Care Products Market Structure and Its Segmentation for the Forecast 2017 2025 - Curious Desk

Skin Stem Cells Comments Off on Medical Skin Care Products Market Structure and Its Segmentation for the Forecast 2017 2025 – Curious Desk | April 16th, 2020

NEW YORK, April 15, 2020 /PRNewswire/ -- The stem cell therapy market was valued at US$ 1,534.55 million in 2019 and is estimated to reach US$ 5,129.66 million by 2027; it is expected to grow at a CAGR of 16.7% from 2020 to 2027.

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The increasing awareness related to the stem cells therapy in effective disease management and growing demand for regenerative medicines are the key factor driving the stem cell therapy market. However, high cost related of the stem cell therapy limits the growth of the market.Stem cell research has been widely investigated globally for various medical applications, especially for the treatment of humans.This raises the importance of creating public awareness about stem cell research and its clinical potential.

The main role of stem cells is in the replacement of dying cells and reconstruction of damaged tissues. Based on the extensive stem cell research, many scientists have claimed that these cells could probably be used in the treatment of various diseases, including cancer and cardiovascular disease.There is a large number of potential treatment procedures that are undergoing clinical trials, and a notably few stem cell therapies have won FDA (i.e., US Food and Drug Administration) approval for clinical usage. For instance, in 2019, the FDA approved Fedratinib for the first-line treatment for myelofibrosis. Moreover, stem cell therapies are widely used in bone marrow transplantation, and these therapies have benefited thousands of people suffering from leukemia. Hematopoietic stem cells are used for treating more than 80 medical diseases, including immune system disorders, blood disorders, neurological disorders, metabolic disorders, genetic disorders, and several types of cancers, such as leukemia and lymphoma; this is also likely to boost the demand for this treatment procedure during the forecast period. Researchers are further investigating the use of stem cell therapies in the treatment of autoimmune disorders.

The global stem cell therapy market has been segmented on the basis of type, treatment, application type, and end user.Based on type, the market has been segmented into adult stem cell therapy, induced pluripotent stem cell therapy, embryonic stem cell therapy, and others.

The adult stem cell therapy held the largest share of the market in 2019; however, induced pluripotent stem cell therapy is estimated to register the highest CAGR in the market during the forecast period.Based on treatment, the stem cell therapy market has been segmented into allogeneic and autologous.

The allogeneic segment held a larger share of the market in 2019; however, the market for the autologous segment is expected to grow at a higher CAGR during the forecast period.Based on application type, the stem cell therapy market has been segmented into musculoskeletal, dermatology, cardiology, drug discovery and development, and other applications.

The musculoskeletal segment held the largest share of the stem cell therapy market in 2019, whereas the drug discovery and development segment is expected to report the highest CAGR during 20202027. Based on end user, the market has been segmented into academic and research institutes, and hospitals and specialty clinics. The academic & research institutes held the largest share of the market in 2019, and it is also expected to report the highest CAGR during the forecast period.Several essential secondary sources referred to for preparing this report are the FDA, World Health Organization (WHO), Organisation for Economic Co-operation and Development, National Institutes of Health, Spanish Agency for Medicines (AEMPS), Japanese Society for Regenerative Medicine, and Indian Council of Medical Research, among others.

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Stem Cell Therapy Market to 2027 - Global Analysis and Forecasts by Type; Treatment; Application; End User, and Geography - Salamanca Press

Bone Marrow Stem Cells Comments Off on Stem Cell Therapy Market to 2027 – Global Analysis and Forecasts by Type; Treatment; Application; End User, and Geography – Salamanca Press | April 16th, 2020

Two-year-old Livia, the child of a Hong Kong mother and German father, is among patients in a London hospital as Britain grapples with a lockdown wrought by the coronavirus. But she is fighting a disease much rarer and even deadlier.

Livia was diagnosed in early March with acute myeloid leukaemia (AML). Because of the coronavirus pandemic, visits to her bedside have been restricted to reduce infection risks.

Only her father can stay with her. Her aunt and grandparents in Hong Kong cannot travel there for fear of exposing the child to more health risks.

Mother Olive Yu, who has been trying every means possible to save her daughter with access to donor registrations delayed during the lockdown told the Post in a phone interview: I still think that I'm in a really bad dream. I still find it very hard to accept that this is happening. Livia is everything to us because shes the only grandchild in the family, and our only child.

We need to be thinking about how we can help give her [as much time] as she can get

Olive Yu, mother

The family has called on those aged between 18 and 60 in Hong Kong to register as a bone marrow donor with the Hong Kong Bone Marrow Donor Registry, led by the Hong Kong Red Cross. The information is shared with the World Marrow Donor Association (WMDA), a global database of volunteer donors.

There are three options to save Livia, and the most ideal one is for a matching donor to be found and a bone marrow transplant to be conducted by June, according to Livias family.

Livias parents are appealing for bone marrow donors. Photo: Handout

Yu said: Everything takes time, especially now with the coronavirus. But the fact is, we are talking about the life of a two-year-old.

Everything is against us, but it doesn't mean that we should just stop and not do anything about it. So were going to try our best and do whatever we can to give her the best chance at life.

As of Wednesday, Britain had recorded more than 93,000 Covid-19 cases, with a death toll of over 12,000. Police enforced a lockdown on March 23, allowing people only to leave their homes for very limited purposes, such as for food and health reasons, and public gatherings of more than two people have been banned, while places such as restaurants, schools, pubs and gyms are closed.

In general, for bone marrow transplants, the donors human leucocyte antigens (HLA), proteins found on the surface of the blood and in tissue cells, must be closely matched so that the recipients body can accept the new stem cells into their bone marrow.

The second option is that the hospital also, at the same time, reaches out to stem cells from mothers who give birth and donate their umbilical cord, Yu added.

The third option is what they call a non-matching donor, which is either from the mother or father.

The blood samples of Livias parents are being analysed for matches, with results pending.

AML is a form of cancer involving the rapid growth of abnormal cells in the bone marrow and blood. This cancer type accounted for less than 1 per cent of all new cancer cases in Britain in 2017, and often occurs in adults, according to Cancer Research UK.

Livia, two, is now warded in a London hospital. Photo: Handout

A haematologist in Hong Kong, who spoke on condition of anonymity, said the incidence of cancer among children aged under 15 is around 1.2 per million. Fewer than 200 children are diagnosed with cancer in Hong Kong each year and about five out of the 200 have AML, according to him.

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Coronavirus: We need bone marrow donors to save my baby girls life from leukaemia, Hong Kong mother of two-year-old pleads amid London lockdown -...

Bone Marrow Stem Cells Comments Off on Coronavirus: We need bone marrow donors to save my baby girls life from leukaemia, Hong Kong mother of two-year-old pleads amid London lockdown -… | April 16th, 2020

In 1994, I thought the biggest challenge in life would be finding a balance between a career as a Senior Trial Partner at a big Dallas firm and raising three children. In 1999, it became clear that the real challenge in my life was much more ominous. I was diagnosed with Multiple Sclerosis. There was no explanation as to why I contracted this devastating disease, what symptoms I would develop, or how fast I would become disabled. Would I be confined to a wheelchair or a bed? Would I become blind or simply have double vision? Would I have pain or just tingling? Would I die? I already had bladder problems, but would I also face bowel dysfunction? Over 2.5 million people are afflicted with MS, so why hasnt anyone found a cure? How could drug companies justify charging over $60,000 a year for medicines that dont improve a patients condition?

For the next fifteen years, I managed the kids and the disease with relative success. I learned what a bladder spasm is and the true definition of the word urgency. I learned that my husband really meant it when he said in sickness and health. I learned that pain from MS included the pain associated with doing a face plant into a door, and spilling boiling water on my leg but being unable to remove my pants before suffering 2nd degree burns. I learned that there were a few advantages to having MS, including speeding through airport security lines because I was in a wheelchair, and always being able to find a parking space.

In 2014 I fell and broke my leg. I was in a wheelchair for 6 weeks. It became obvious that it was time to become more aggressive with treatments. After scouring the internet for every treatment for MS in the world, I identified Dr. Dimitrios Karussis at Hadassah Medical Organization in Israel as my best hope. His approach was still experimental. He used the patients own stem cells, obtained through bone marrow extraction, grew the cells, and then infused the cells through a spinal tap.

After eight infusions the benefits of the treatment are unmistakable. Because I still walk with a walker, people realize that Im not cured. What they dont know is that I have my life back. Ive written three books, volunteer regularly at a hospital, travel around the country to raise awareness and financial support for the incredible work of Hadassah, the Womens Zionist Organization of America, Inc. (HWZOA) who operate Hadassah Hospital in Israel. I cook every week for my daughter in medical school. I have attended the graduation ceremonies of each of my three children from college, and I attended the wedding of my oldest son recently. This past year, we celebrated Thanksgiving at my house with 37 relatives.

Having MS has allowed me to stop sweating the small stuff. I have come to realize that what makes me happiest is making others happy. At the Dallas Childrens Hospital where I volunteer, my disability gives me the advantage of having an immediate connection to the kids. Making people smile is the best job at the hospital.

David Ben Gurion said: In Israel, in order to be a realist, you must believe in miracles.

I am a realist. I didnt simply wish to be cured of MS. I researched the possible options for treatment and used my best judgment to select one. Dr. Karussis is also a realist. Hes devoted over 30 years researching stem cell treatment of neurological diseases. He has published more than 120 peer reviewed scientific papers, given more than 150 lectures, served on editorial boards of major medical journals, was elected as the President of the Israeli Neuroimmunological Society and hosted an International Neurological Meeting. He has published the amazing results of the stem cell therapy he formulated for the treatment of MS and ALS.

I also believe in miracles. The miracle is that the people of Hadassah Hospital in Israel have given of their time, talent, and money to make this treatment possible and available to me. The miracle is that studies that I volunteered for twenty years ago in Dallas made me an attractive candidate for Dr. Karussis research. The miracle is that the Israeli Ministry of Health approved me to be treated in their Compassionate Care program. The miracle is that all MS patients can now have hope that an effective treatment is here and Hadassah Hospital is sharing it with the world.

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A Realist Who Believes in Miracles - Thrive Global

Bone Marrow Stem Cells Comments Off on A Realist Who Believes in Miracles – Thrive Global | April 16th, 2020

'), link: "https://www.rt.com/shows/documentary/486023-donors-blood-sisters-brothers/" }, events: { onReady: function () { if(ga && mediaMute === false) { ga('send', 'event', 'JWPLAYER-GA', 'CLICK PLAY', location.href); ga('send', 'event', 'JW Player Article', 'Ready', location.href); // } }, onPlay: function () { myStreamingTag.playVideoContentPart(metadata); if (ga) { if (mediaMute === false) { ga('send', 'event', 'JWPLAYER-GA', 'CLICK PLAY', location.href); ga('send', 'event', 'JW Player Article', 'Play', location.href); } } var playingVideoId = 'js-mediaplayer-5e985e5520302765572ed72c'; // id pauseMedia(playingVideoId); // if (recomedationBlock5e985e5520302765572ed72c) { recomedationBlock5e985e5520302765572ed72c.classList.remove('recomendation_active'); } if (mediaplayerContainer5e985e5520302765572ed72c) { mediaplayerContainer5e985e5520302765572ed72c.classList.add('mediaplayer_played'); } localStorage.setItem('canfixed', true); }, onPause: function () { myStreamingTag.stop(); if (mediaMute === false) { if (ga) ga('send', 'event', 'JWPLAYER-GA', 'CLICK PAUSE', location.href); } if (recomedationBlock5e985e5520302765572ed72c) { recomedationBlock5e985e5520302765572ed72c.classList.add('recomendation_active'); } }, onComplete: function () { myStreamingTag.stop(); if (ga && mediaMute === false) { ga('send', 'event', 'JWPLAYER-GA', 'COMPLETE', location.href); ga('send', 'event', 'JW Player Article', 'Complete', location.href); } if (recomedationBlock5e985e5520302765572ed72c) { recomedationBlock5e985e5520302765572ed72c.classList.add('recomendation_active'); } } } }); jwplayer("js-mediaplayer-5e985e5520302765572ed72c").addButton( "https://www.rt.com/static/libs/jwplayer/img/download.png", "Download", function () { window.location.href = "https://cdnv.rt.com/files/2020.04/5e985e5520302765572ed72c.mp4?download=1"; }, "download" ); function pauseMedia(playingMediaId) { var players = document.querySelectorAll('.jwplayer, object'); var fixPlayer = document.querySelector('.mediaplayer_fixed'); let shadowDiv = document.querySelector('.div_shadow'); var plId = playingMediaId.split('-')[2]; for (var i = 0, max = players.length; i

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You're my type: The donor lottery - RT

Bone Marrow Stem Cells Comments Off on You’re my type: The donor lottery – RT | April 16th, 2020

Researchers at Lund University in Sweden have succeeded in restoring mobility and sensation of touch in stroke-afflicted rats by reprogramming human skin cells to become nerve cells, which were then transplanted into the rats' brains. The study has now been published in the Proceedings of the National Academy of Sciences (PNAS).

"Six months after the transplantation, we could see how the new cells had repaired the damage that a stroke had caused in the rats' brains," says Professor Zaal Kokaia, who together with senior professor Olle Lindvall and researcher Sara Palma-Tortosa at the Division of Neurology is behind the study.

Several previous studies from the Lund team and others have shown that it is possible to transplant nerve cells derived from human stem cells or from reprogrammed cells into brains of rats afflicted by stroke. However, it was not known whether the transplanted cells can form connections correctly in the rat brain in a way that restores normal movement and feeling.

"We have used tracking techniques, electron microscopy and other methods, such as light to switch off activity in the transplanted cells, as a way to show that they really have connected correctly in the damaged nerve circuits. We have been able to see that the fibres from the transplanted cells have grown to the other side of the brain, the side where we did not transplant any cells, and created connections. No previous study has shown this," says Zaal Kokaia, who, even though he and colleague Olle Lindvall have studied the brain for several decades, is surprised by the results.

"It is remarkable to find that it is actually possible to repair a stroke-damaged brain and recreate nerve connections that have been lost. The study kindles hope that in the future it could be possible to replace dead nerve cells with new healthy nerve cells also in stroke patients, even though there is a long way to go before achieving that," says Olle Lindvall.

The researchers have used human skin cells that have been reprogrammed in the laboratory to become nerve cells. They were then transplanted into the cerebral cortex of rats, in the part of the brain that is most often damaged after a stroke. Now the researchers will undertake further studies.

"We want to know more about how the transplanted cells affect the opposite hemisphere of the brain. We also want to take a closer look at how a transplant affects intellectual functions such as memory. In addition, we will study possible side effects. Safety is, of course, extremely important for cell transplantation if it is going to be used clinically in the future," says Zaal Kokaia.

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Researchers Have Succeeded in Restoring Mobility and Sensation of Touch in Stroke-Afflicted Rats - Technology Networks

Skin Stem Cells Comments Off on Researchers Have Succeeded in Restoring Mobility and Sensation of Touch in Stroke-Afflicted Rats – Technology Networks | April 15th, 2020

NEW YORK, April 15, 2020 /PRNewswire/ -- The stem cell therapy market was valued at US$ 1,534.55 million in 2019 and is estimated to reach US$ 5,129.66 million by 2027; it is expected to grow at a CAGR of 16.7% from 2020 to 2027.

Read the full report: https://www.reportlinker.com/p05882135/?utm_source=PRN

The increasing awareness related to the stem cells therapy in effective disease management and growing demand for regenerative medicines are the key factor driving the stem cell therapy market. However, high cost related of the stem cell therapy limits the growth of the market.Stem cell research has been widely investigated globally for various medical applications, especially for the treatment of humans.This raises the importance of creating public awareness about stem cell research and its clinical potential.

The main role of stem cells is in the replacement of dying cells and reconstruction of damaged tissues. Based on the extensive stem cell research, many scientists have claimed that these cells could probably be used in the treatment of various diseases, including cancer and cardiovascular disease.There is a large number of potential treatment procedures that are undergoing clinical trials, and a notably few stem cell therapies have won FDA (i.e., US Food and Drug Administration) approval for clinical usage. For instance, in 2019, the FDA approved Fedratinib for the first-line treatment for myelofibrosis. Moreover, stem cell therapies are widely used in bone marrow transplantation, and these therapies have benefited thousands of people suffering from leukemia. Hematopoietic stem cells are used for treating more than 80 medical diseases, including immune system disorders, blood disorders, neurological disorders, metabolic disorders, genetic disorders, and several types of cancers, such as leukemia and lymphoma; this is also likely to boost the demand for this treatment procedure during the forecast period. Researchers are further investigating the use of stem cell therapies in the treatment of autoimmune disorders.

The global stem cell therapy market has been segmented on the basis of type, treatment, application type, and end user.Based on type, the market has been segmented into adult stem cell therapy, induced pluripotent stem cell therapy, embryonic stem cell therapy, and others.

The adult stem cell therapy held the largest share of the market in 2019; however, induced pluripotent stem cell therapy is estimated to register the highest CAGR in the market during the forecast period.Based on treatment, the stem cell therapy market has been segmented into allogeneic and autologous.

The allogeneic segment held a larger share of the market in 2019; however, the market for the autologous segment is expected to grow at a higher CAGR during the forecast period.Based on application type, the stem cell therapy market has been segmented into musculoskeletal, dermatology, cardiology, drug discovery and development, and other applications.

The musculoskeletal segment held the largest share of the stem cell therapy market in 2019, whereas the drug discovery and development segment is expected to report the highest CAGR during 20202027. Based on end user, the market has been segmented into academic and research institutes, and hospitals and specialty clinics. The academic & research institutes held the largest share of the market in 2019, and it is also expected to report the highest CAGR during the forecast period.Several essential secondary sources referred to for preparing this report are the FDA, World Health Organization (WHO), Organisation for Economic Co-operation and Development, National Institutes of Health, Spanish Agency for Medicines (AEMPS), Japanese Society for Regenerative Medicine, and Indian Council of Medical Research, among others.

Read the full report: https://www.reportlinker.com/p05882135/?utm_source=PRN

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Stem Cell Therapy Market to 2027 - Global Analysis and Forecasts by Type; Treatment; Application; End User, and Geography - Yahoo Finance

Bone Marrow Stem Cells Comments Off on Stem Cell Therapy Market to 2027 – Global Analysis and Forecasts by Type; Treatment; Application; End User, and Geography – Yahoo Finance | April 15th, 2020

EL SEGUNDO, Calif.--(BUSINESS WIRE)-- NantKwest, Inc. (NASDAQ: NK) and ImmunityBio, Inc., clinical-stage immunotherapy companies within the NantWorks family of companies, today announced they are in active discussions with the U.S. Food and Drug Administration (FDA) for vaccines and therapeutics to combat COVID-19.

Leveraging ImmunityBios expertise in vaccine development and natural killer cell activation, with a broad platform of immunomodulators currently in clinical trials for cancer and infectious diseases, and NantKwests extensive experience in off-the-shelf, cell-based therapeutics, the companies are combining their resources to design and develop therapeutics and vaccines for COVID-19.

Were in a race against time, but I am confident that, as a result of the incredible hard work the NantKwest, ImmunityBio, and the global scientific communities are undertaking, we will find effective therapeutics and vaccines against this coronavirus, said Patrick Soon-Shiong, M.D., Chairman & CEO of NantKwest and ImmunityBio.

Therapeutics:

The biological, immunological, and physiological status of the patients medical state should inform the treatment strategy to reverse the infectivity and tissue damage caused by this virus. ImmunityBio and NantKwest have developed immunomodulator regimens for COVID-19 based on the biological stage of the patients infection - from the mild, moderate to the severe or critically ill state.

In the mild-to-moderate stage of infection, we believe that the patients infection and viral load could be mitigated with natural killer (NK) and T cell stimulation. Hence, in this early-moderate stage of the disease, we are proposing clinical trials of N-803 alone, and a second trial of haNK alone, or haNK combined with convalescent plasma, said Dr. Soon-Shiong.

Investigational New Drug (IND) applications with the FDA for these trials are pending. ImmunityBios Il-15 superagonist N-803 is currently being used in clinical trials for other indications and has achieved Breakthrough Therapy Designation from the FDA[1] for the treatment of BCG-unresponsive non-muscle invasive bladder carcinoma in situ (NMIBC-CIS) patients. It has also demonstrated encouraging results in lowering the viral load in SHIV-infected monkeys[2], as announced last month at the Annual Conference on Retroviruses and Opportunistic Infections (CROI)[3].

In patients requiring ventilatory support in the severe state of COVID-19 disease, we are exploring the use of bone marrow-derived allogenic mesenchymal stem cells (BM-Allo-MSC) to mitigate the cytopathic storm, said Dr. Soon-Shiong.

NantKwest has proprietary isolation and expansion methods for growing MSCs and is using ImmunityBios automated, closed system (GMP-in-a-Box) to safely and rapidly grow these stem cells from a bone marrow cell bank in approximately 7-9 days. NantKwest has filed an IND with the FDA and anticipates beginning trials in Q2 2020.

Vaccines: Developing a platform for both initial immunizations and subsequent booster injections

First generation Adenovirus platforms (Ad5) currently in use are disadvantaged by inducing adenovirus neutralizing antibodies, thus limiting multiple doses and reducing the immune response to the antigen of interest. ImmunityBio has overcome this obstacle through the development of a second generation Ad5 platform. Through multiple deletions in the adenovirus genome, this next generation platform establishes a vector that is immunologically quiet as it relates to adenovirus protein production in the host dendritic cell and enables this same Ad5 vector to serve both as a prime and a boost treatment, even in patients with pre-existing adenovirus immunity. This second-generation Ad5 [E1-, E2b-, E3- deleted] platform has demonstrated safety in Phase I and Phase II studies in immunosuppressed cancer patients.

Furthermore ImmunityBio has extensive infectious disease experience with this second generation Ad5 platform and has published several peer-reviewed articles on studies demonstrating humoral and cell mediated immunity in H1N1 Influenza[4], HIV[5], SIV[6], Lassa Fever[7], Chikungunya, and Zika virus infections.

While development of therapies is urgently needed in this crisis, as urgent is the need to develop a vaccine with long-lasting cell-mediated immunity. Developing vaccines in the time of pandemics requires novel approaches and the use of modernized genomics, molecular dynamics, and vectors that are proven to induce cell-mediated immunity, with mass scale production capabilities. In 2009, with the H1N1 crisis, the scientific team developing this second generation Ad5 platform demonstrated that such a vaccine for the H1N1 pandemic could be developed in six weeks from identification of the H1N1 sequence. This experience in 2009 allows ImmunityBio to respond as rapidly as possible to the COVID-19 pandemic, continued Dr. Soon-Shiong. I view the spike (S) protein and the nucleocapsid (N) protein as the equivalent of a neoantigen in cancer. A recent study by the National Cancer Institute (NCI) in patients with advanced cancer, published in The Oncologist[8] reported positive evidence that this platform could induce antigen-specific T cell immunity, even in the face of previous adenoviral immunity, said Dr. Soon-Shiong. Together with our scientific collaborators at the NCI, we have recently published evidence[9] that the Ad5 platform can successfully induce cell-mediated immunity following the administration of Ad5-Neoantigens, with total remission of the tumor in pre-clinical models. Based on these findings, we are hopeful that the Ad platform could induce a similar immune response to this novel Coronavirus antigen.

About NantKwest

NantKwest (NASDAQ: NK) is an innovative, clinical-stage immunotherapy company focused on harnessing the power of the innate immune system to treat cancer and virally-induced infectious diseases. NantKwest is the leading producer of clinical dose forms of off-the-shelf natural killer (NK) cell therapies. The activated NK cell platform is designed to destroy cancer and virally-infected cells. The safety of these optimized, activated NK cellsas well as their activity against a broad range of cancershas been tested in phase I clinical trials in Canada and Europe, as well as in multiple phase I and II clinical trials in the United States. By leveraging an integrated and extensive genomics and transcriptomics discovery and development engine, together with a pipeline of multiple, clinical-stage, immuno-oncology programs, NantKwests goal is to transform medicine by delivering living drugs-in-a-bag and bringing novel NK cell-based therapies to routine clinical care. NantKwest is a member of the NantWorks ecosystem of companies. For more information, please visit http://www.nantkwest.com

haNK is a registered trademark of NantKwest, Inc.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include statements concerning or implying that NantKwest will be successful in improving the treatment of cancer. Risks and uncertainties related to this endeavor include, but are not limited to, obtaining FDA approval of NantKwests NK cells as well as other therapeutics as part of the NANT Cancer Vaccine platform as a cancer treatment.

Forward-looking statements are based on managements current expectations and are subject to various risks and uncertainties that could cause actual results to differ materially and adversely from those expressed or implied by such forward-looking statements. Accordingly, these forward-looking statements do not constitute guarantees of future performance, and you are cautioned not to place undue reliance on these forward-looking statements.

These and other risks regarding NantKwests business are described in detail in its Securities and Exchange Commission filings, including in NantKwests Annual Report on Form 10-K for the year ended December 31, 2019. These forward-looking statements speak only as of the date hereof, and we disclaim any obligation to update these statements except as may be required by law.

About ImmunityBio

ImmunityBio, Inc. is a privately-held immunotherapy company with a broad portfolio of biological molecules at clinical stages of development. The companys goals are to employ this portfolio to activate endogenous natural killer and CD8+ T cells in the fields of cancer and infectious disease. Specifically, ImmunityBios goal is to develop a memory T-cell cancer vaccine to combat multiple tumor typeswithout the use of high-dose chemotherapy. Regarding infectious disease, ImmunityBio is addressing HIV, influenza, and the coronavirus.

ImmunityBios first-in-human platform of technologies has enabled it to achieve one of the most comprehensive, late-stage clinical pipelines, activating both the innate (natural killer cell) and adaptive immune systems. The product pipeline includes an albumin-linked chemotherapeutic (Aldoxorubicin), a novel IL-15 cytokine superagonist (N-803), checkpoint inhibitors, macrophage polarizing peptides, bi-specific fusion proteins targeting TGFb and IL-12, adenovirus, and yeast vaccine therapies targeting tumor-associated antigens and neoepitopes.

In December 2019, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation to N-803 for BCG-unresponsive CIS non-muscle invasive bladder cancer (NMIBC). Other indications currently at registration-stage trials include BCG-unresponsive papillary bladder cancer, first- and second-line lung cancer, and metastatic pancreatic cancer.

ImmunityBios goal is to develop therapies, including vaccines, for the prevention and treatment of HIV, influenza, and the coronavirus SARS-CoV-2.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include statements concerning or implying that ImmunityBio will be successful in improving the treatment of various diseases, including, but not limited to the novel coronavirus and cancer. Risks and uncertainties related to this endeavor include, but are not limited to, the companys beliefs regarding the success, cost and timing of its development activities and clinical trials.

Forward-looking statements are based on managements current expectations and are subject to various risks and uncertainties that could cause actual results to differ materially and adversely from those expressed or implied by such forward-looking statements. Accordingly, these forward-looking statements do not constitute guarantees of future performance, and you are cautioned not to place undue reliance on these forward-looking statements. These forward-looking statements speak only as of the date hereof, and we disclaim any obligation to update these statements except as may be required by law.

[1]: ImmunityBio Granted FDA Breakthrough Therapy Designation for N-803 IL-15 Superagonist in NMIBC December 4, 2019 https://www.businesswire.com/news/home/20191204005300/en/ImmunityBio-Granted-FDA-Breakthrough-Therapy-Designation-N-803

[2]: ImmunityBio Announces Durable Virus Control of SHIV Without Anti-Retroviral Therapy (ART) by Activating NK and Memorty T Cells with N-803, an IL-15 Superagonist March 10, 2020 https://immunitybio.com/immunitybio-announces-durable-virus-control-of-shiv-without-anti-retroviral-therapy-by-activating-nk-and-memory-t-cells-with-n-803-an-il-15-superagonist/

[3]: Combination IL-15 Therapy in a SHIV NHP Model Presented at Conference on Retroviruses and Opportunistic Infections (CROI) March 8-11, 2020 Boston, Massachusetts http://www.croiconference.org/sessions/combination-il-15-therapy-shiv-nhp-model

[4]: Prevention of Influenza Virus Shedding and Protection from Lethal H1N1 Challenge Using a Consensus 2009 H1N1 HA and NA Adenovirus Vector Vaccine. Vaccine. 2011 Sep 16; 29(40): 70207026. Published 2011 Aug 5. doi: 10.1016/j.vaccine.2011.07.073

[5]: Induction and Comparison of SIV Immunity in Ad5 Nave and Ad5 Immne Non-Human Primates Using an Ad5 [E1-, E2b-] Based Vaccine. Vaccine. 2011 Oct 19;29(45):8101-7. doi: 10.1016/j.vaccine.2011.08.038. Epub 2011 Aug 22.

[6]: Control of SIV Infection and Subsequent Induction of Pandemic H1N1 Immunity in Rhesus Macaques Using an Ad5 [E1-, E2b-] Vector Platform.Vaccine. 2012 Nov 26; 30(50): 72657270. Published 2012 Oct 2. doi: 10.1016/j.vaccine.2012.09.058

[7]: Adenoviral Vector-Based Vaccine is Fully Protective Against Lethal Lassa Fever Vhallenge in Hartley Guinea Pigs. Vaccine..2019 Oct 23;37(45):6824-6831. doi: 10.1016/j.vaccine.2019.09.030. Epub 2019 Sep 24.

[8]: A Phase I Trial Using a Multitargeted Recombinant Adenovirus 5 (CEA/MUC1/Brachyury)Based Immunotherapy Vaccine Regimen in Patients with Advanced Cancer. The Oncol. doi:10.1634/theoncologist.2019-0608

[9]: Efficient Tumor Clearance and Diversified Immunity Through Neoepitope Vaccines and Combinatorial Immunotherapy. Cancer Immunology Research July 2019 DOI: 10.1158/2326-6066.CIR-18-0620

View source version on businesswire.com: https://www.businesswire.com/news/home/20200414005353/en/

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NantKwest and ImmunityBio Announce Therapeutics and Vaccines for Combatting COVID-19; Clinical Trials Anticipated to Begin This Quarter - BioSpace

Bone Marrow Stem Cells Comments Off on NantKwest and ImmunityBio Announce Therapeutics and Vaccines for Combatting COVID-19; Clinical Trials Anticipated to Begin This Quarter – BioSpace | April 15th, 2020

News Release

Wednesday, April 15, 2020

NIH-funded study offers new path to modeling eye disease, advancing therapies

Researchers have discovered a technique for directly reprogramming skin cells into light-sensing rod photoreceptors used for vision. The lab-made rods enabled blind mice to detect light after the cells were transplanted into the animals eyes. The work, funded by the National Eye Institute (NEI), published April 15 in Nature. The NEI is part of the National Institutes of Health.

Up until now, researchers have replaced dying photoreceptors in animal models by creating stem cells from skin or blood cells, programming those stem cells to become photoreceptors, which are then transplanted into the back of the eye. In the new study, scientists show that it is possible to skip the stem-cell intermediary step and directly reprogram skins cells into photoreceptors for transplantation into the retina.

This is the first study to show that direct, chemical reprogramming can produce retinal-like cells, which gives us a new and faster strategy for developing therapies for age-related macular degeneration and other retinal disorders caused by the loss of photoreceptors, said Anand Swaroop, Ph.D., senior investigator in the NEI Neurobiology, Neurodegeneration, and Repair Laboratory, which characterized the reprogrammed rod photoreceptor cells by gene expression analysis.

Of immediate benefit will be the ability to quickly develop disease models so we can study mechanisms of disease. The new strategy will also help us design better cell replacement approaches, he said.

Scientists have studied induced pluripotent stem (iPS) cells with intense interest over the past decade. IPSCs are developed in a lab from adult cells rather than fetal tissue and can be used to make nearly any type of replacement cell or tissue. But iPS cell reprogramming protocols can take six months before cells or tissues are ready for transplantation. By contrast, the direct reprogramming described in the current study coaxed skin cells into functional photoreceptors ready for transplantation in only 10 days. The researchers demonstrated their technique in mouse eyes, using both mouse- and human-derived skin cells.

Our technique goes directly from skin cell to photoreceptor without the need for stem cells in between, said the studys lead investigator, Sai Chavala, M.D., CEO and president of CIRC Therapeutics and the Center for Retina Innovation. Chavala is also director of retina services at KE Eye Centers of Texas and a professor of surgery at Texas Christian University and University of North Texas Health Science Center (UNTHSC) School of Medicine, Fort Worth.

Direct reprogramming involves bathing the skin cells in a cocktail of five small molecule compounds that together chemically mediate the molecular pathways relevant for rod photoreceptor cell fate. The result are rod photoreceptors that mimic native rods in appearance and function.

The researchers performed gene expression profiling, which showed that the genes expressed by the new cells were similar to those expressed by real rod photoreceptors. At the same time, genes relevant to skin cell function had been downregulated.

The researchers transplanted the cells into mice with retinal degeneration and then tested their pupillary reflexes, which is a measure of photoreceptor function after transplantation. Under low-light conditions, constriction of the pupil is dependent on rod photoreceptor function. Within a month of transplantation, six of 14 (43%) animals showed robust pupil constriction under low light compared to none of the untreated controls.

Moreover, treated mice with pupil constriction were significantly more likely to seek out and spend time in dark spaces compared with treated mice with no pupil response and untreated controls. Preference for dark spaces is a behavior that requires vision and reflects the mouses natural tendency to seek out safe, dark locations as opposed to light ones.

Even mice with severely advanced retinal degeneration, with little chance of having living photoreceptors remaining, responded to transplantation. Such findings suggest that the observed improvements were due to the lab-made photoreceptors rather than to an ancillary effect that supported the health of the hosts existing photoreceptors, said the studys first author Biraj Mahato, Ph.D., research scientist, UNTHSC.

Three months after transplantation, immunofluorescence studies confirmed the survival of the lab-made photoreceptors, as well as their synaptic connections to neurons in the inner retina.

Further research is needed to optimize the protocol to increase the number of functional transplanted photoreceptors.

Importantly, the researchers worked out how this direct reprogramming is mediated at the cellular level. These insights will help researchers apply the technique not only to the retina, but to many other cell types, Swaroop said.

If efficiency of this direct conversion can be improved, this may significantly reduce the time it takes to develop a potential cell therapy product or disease model, said Kapil Bharti, Ph.D., senior investigator and head of the Ocular and Stem Cell Translational Research Section at NEI.

Chavala and his colleagues are planning a clinical trial to test the therapy in humans for degenerative retinal diseases, such as retinitis pigmentosa.

The work was supported by grants EY021171, EY025667, EY025905, and EY025717 and NEI Intramural Research Program grants ZIAEY000450, ZIAEY000474 and ZIAEY000546.

The University of North Texas has a patent pending on the chemical reprogramming method reported in this paper. CIRC Therapeutics is a start-up company that plans to commercialize treatments using the technology.

This press release describes a basic research finding. Basic research increases our understanding of human behavior and biology, which is foundational to advancing new and better ways to prevent, diagnose, and treat disease. Science is an unpredictable and incremental process each research advance builds on past discoveries, often in unexpected ways. Most clinical advances would not be possible without the knowledge of fundamental basic research.

NEI leads the federal governments research on the visual system and eye diseases. NEI supports basic and clinical science programs to develop sight-saving treatments and address special needs of people with vision loss. For more information, visit https://www.nei.nih.gov.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

Mahato B, Kaya KD , Fan Y, Sumien N, Shetty RA, Zhang W, Davis D, Mock T , Batabyal S, Ni A, Mohanty S, Han Z, Farjo R, Forster M, Swaroop A and Chavala SH. Pharmacologic fibroblast reprogramming into photoreceptors restores vision. Published online April 15, 2020 in Nature.http://dx.doi.org/10.1038/s41586-020-2201-4

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Researchers restore sight in mice by turning skin cells into light-sensing eye cells - National Institutes of Health

IPS Cell Therapy Comments Off on Researchers restore sight in mice by turning skin cells into light-sensing eye cells – National Institutes of Health | April 15th, 2020

Advance Market Analyticsreleased the research report ofGlobal Liver CirrhosisMarket, offers a detailed overview of the factors influencing the global business scope.Global Liver Cirrhosis Market research report shows the latest market insights with upcoming trends and breakdown of the products and services.The report provides key statistics on the market status, size, share, growth factors of the Global Liver Cirrhosis.This Report covers the emerging players data, including: competitive situation, sales, revenue and global market share of top manufacturers are F. Hoffmann-La Roche AG (Switzerland), Merck & Co., Inc (United States), Abbott Laboratories (United States), Novartis International AG (Switzerland), Bristol Myers Squibb Company (United States), Gilead Sciences, Inc (United States), Conatus Pharmaceuticals (United States), GlaxoSmithKline plc (United Kingdom), Grifols, S.A. (Spain), GWOXI Stem Cell Applied Technology Co., Ltd (China), Hepion Pharmaceuticals (United States), Intercept Pharmaceuticals, Inc. (United States) and Lepu Medical Technology (Beijing) Co., Ltd. (China).

Free Sample Report + All Related Graphs & Charts @ https://www.advancemarketanalytics.com/sample-report/63193-global-liver-cirrhosis-market

The liver cirrhosis means the condition that causes scar tissue of the liver to replace healthy liver tissue cells, it happens over the period due to the chronic infection or alcohol addiction. It is diagnosed by various radiology tests such as computed tomography (CT), ultrasound, magnetic resonance imaging (MRI), needle biopsy of the liver. A new imaging technique called elastography, which can be performed with ultrasound or MRI, can also diagnosis cirrhosis.

Market Trend

Market Drivers

Opportunities

Restraints

Challenges

The Global Liver Cirrhosisis segmented by following Product Types:

Type (Alcoholic Cirrhosis, Atrophic Cirrhosis, Biliary Cirrhosis, Cardiac Cirrhosis, Cryptogenic Cirrhosis), Application (Hospitals, Specialty Clinics, Others), Treatment (Self-care, Medications {Diuretic, Ammonia Reducer, Beta Blocker, Antibiotics, Antiviral Drug}, Medical procedure {Rubber Band Ligation, Therapeutic Endoscopy, and Transjugular Intrahepatic Portosystemic Shunt}, Surgery {Liver transplantation}), Stages (Stage 1, Stage 2, Stage 3, Stage 4), Tests (Computed Tomography (CT), Ultrasound, Magnetic Resonance Imaging (MRI), Needle Biopsy)

Region Included are: North America, Europe, Asia Pacific, Oceania, South America, Middle East & Africa

Country Level Break-Up: United States, Canada, Mexico, Brazil, Argentina, Colombia, Chile, South Africa, Nigeria, Tunisia, Morocco, Germany, United Kingdom (UK), the Netherlands, Spain, Italy, Belgium, Austria, Turkey, Russia, France, Poland, Israel, United Arab Emirates, Qatar, Saudi Arabia, China, Japan, Taiwan, South Korea, Singapore, India, Australia and New Zealand etc.Enquire for customization in Report @:https://www.advancemarketanalytics.com/enquiry-before-buy/63193-global-liver-cirrhosis-market

Strategic Points Covered in Table of Content of Global Liver Cirrhosis Market:

Chapter 1: Introduction, market driving force product Objective of Study and Research Scope the Global Liver Cirrhosis market

Chapter 2: Exclusive Summary the basic information of the Global Liver Cirrhosis Market.

Chapter 3: Displayingthe Market Dynamics- Drivers, Trends and Challenges of the Global Liver Cirrhosis

Chapter 4: Presenting the Global Liver Cirrhosis Market Factor Analysis Porters Five Forces, Supply/Value Chain, PESTEL analysis, Market Entropy, Patent/Trademark Analysis.

Chapter 5: Displaying the by Type, End User and Region 2013-2018

Chapter 6: Evaluating the leading manufacturers of the Global Liver Cirrhosis market which consists of its Competitive Landscape, Peer Group Analysis, BCG Matrix & Company Profile

Chapter 7: To evaluate the market by segments, by countries and by manufacturers with revenue share and sales by key countries in these various regions.

Chapter 8 & 9: Displaying the Appendix, Methodology and Data Source

Finally, Global Liver Cirrhosis Market is a valuable source of guidance for individuals and companies.

Data Sources & Methodology

The primary sources involves the industry experts from the Global Liver Cirrhosis Market including the management organizations, processing organizations, analytics service providers of the industrys value chain. All primary sources were interviewed to gather and authenticate qualitative & quantitative information and determine the future prospects.

In the extensive primary research process undertaken for this study, the primary sources Postal Surveys, telephone, Online & Face-to-Face Survey were considered to obtain and verify both qualitative and quantitative aspects of this research study. When it comes to secondary sources Companys Annual reports, press Releases, Websites, Investor Presentation, Conference Call transcripts, Webinar, Journals, Regulators, National Customs and Industry Associations were given primary weight-age.

Get More Information: https://www.advancemarketanalytics.com/reports/63193-global-liver-cirrhosis-market

Thanks for reading this article; you can also get individual chapter wise section or region wise report version like North America, Europe or Asia.

About Author:

Advance Market Analytics is Global leaders of Market Research Industry provides the quantified B2B research to Fortune 500 companies on high growth emerging opportunities which will impact more than 80% of worldwide companies revenues.

Our Analyst is tracking high growth study with detailed statistical and in-depth analysis of market trends & dynamics that provide a complete overview of the industry. We follow an extensive research methodology coupled with critical insights related industry factors and market forces to generate the best value for our clients. We Provides reliable primary and secondary data sources, our analysts and consultants derive informative and usable data suited for our clients business needs. The research study enable clients to meet varied market objectives a from global footprint expansion to supply chain optimization and from competitor profiling to M&As.

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Liver Cirrhosis Market Projected to Gain Significant Value by 2024 - Science In Me

Cardiac Stem Cells Comments Off on Liver Cirrhosis Market Projected to Gain Significant Value by 2024 – Science In Me | April 15th, 2020

The coronavirus pandemic has gripped all countries and infected more than half a million people around the world, so far. Some 100,000 people have also lost their lives to the virus. In Iran, too, all national plans have been drawn up while taking the epidemic into consideration.

The Royan Research Institute, which is a distinguished scientific centre in Iran, is naturally expected to adopt innovative measures in order to boost the societys health at a time when the country is gripped by the coronavirus outbreak. One of the measures for which the research centre is known is its cell-therapy capacity. Recently, Royan has taken action to tap into its cell-therapy potential to fight COVID-19.

Head of the research centre Abdolhossein Shahverdi has, in an interview, weighed in on the measures adopted by the institute to fight the coronavirus, namely the establishment of a molecular diagnostic laboratory.

The Royan Institute has good experience in the field of cell science, he said.

Given that the Royan Research Centre has the necessary infrastructure, we felt that we should tap into its potentialities to help tackle the ordeal which has gripped the country, he added.

Of course, treatments offered by the Royan Institute has, so far, been mostly related to infertility or cell-therapy for hardly curable diseases; however, there was good infrastructure at Roya, and with reliance on this very infrastructure, we began to put into service a molecular diagnosis lab in cooperation with the Ministry of Health and Medical Education to serve as a backup coronavirus diagnosis laboratory, he said.

One of the problems that develop in patients infected with the coronavirus is that their lungs are affected, and these problems may result in subsequent complications. So far, good treatment methods have been used for COVID-19 patients in Iran by drawing on Chinas experience in fighting the coronavirus as well as the findings of medical institutes inside Iran. In addition, a large percentage of patients have recovered using these very methods and returned to the bosom of their families.

he Royan Research Institute has experience in the field of cell therapy and using Mesenchymal stem cells (MSCs). The institute has a record of treating different illnesses using cell therapy. Mesenchymal stem cells are among good cells used in cell therapy and play a role in moderating reactions by the immune system and healing damaged tissue. The research institute has received initial licenses from the Ministry of Health and Medical Treatment to use MSCs. By drawing on its experience in cell therapy and its treatment record in that regard, the Royan Institute has taken the first step in developing a treatment for coronavirus patients through cell therapy and stem cells in cooperation with other hospitals and the Tehran University of Medical Sciences.

In this treatment method, MSCs are used. One of the sources of these cells are umbilical cord blood cells or marrow cells, he noted.

In the past, we had used these cells to treat some incurable illnesses such as cartilage and bone diseases, and we achieved good results, said the director of the institute.He expressed hope the treatment method will successfully pass the stage of clinical tests and prove useful in treating coronavirus patients.

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Stem-Cell-Therapy Proves Effective in Treating COVID-19 - Iran Front Page - IFP News

Bone Marrow Stem Cells Comments Off on Stem-Cell-Therapy Proves Effective in Treating COVID-19 – Iran Front Page – IFP News | April 14th, 2020

In this special edition of the CURE Talks Cancer podcast, we teamed up with our sister publication OncLive on Air to speak with a patient-doctor duo on myeloproliferative neoplasms.

BY Kristie L. Kahl and Gina Columbus

MPNS essential thrombocythemia, myelofibrosis and polycythemia vera begin with an abnormal change, or mutation, in a stem cell in the bone marrow, which leads to an overproduction of any combination of white cells, red cells and platelets.

In this special edition of the CURE Talks Cancer podcast, we teamed up with our sister publication OncLive on Air to speak with a patient-doctor duo on the disease.

Learn more from Dr. Ruben A. Mesa, director of the Mays Cancer Center at UT Health San Antonio MD Anderson, and Antje Hjerpe, a patient diagnosed with essential thrombocythemia in 1992. The pair discuss myeloproliferative neoplasms what they are, how theyre treated and how patients can talk to their doctors to be their own best advocates.

See the rest here:
Patient-Doctor Duo: The Basics of Myeloproliferative Neoplasms - Curetoday.com

Bone Marrow Stem Cells Comments Off on Patient-Doctor Duo: The Basics of Myeloproliferative Neoplasms – Curetoday.com | April 14th, 2020

captionStress may cause gray hair prematurely.sourceManop_Phimsit/Shutterstock

Stress can affect the body in many different ways. And while it seems that stressful life events like being president may cause gray hair, the truth is a bit more complicated.

Gray hair is likely caused by a combination of genetics, aging, and hormones, and there is some research to suggest that stress can turn hair gray prematurely. Heres what you need to know.

When youre born, your hair color is determined by natural pigments in your skin called melanin.

Human hair follicles contain two types of melanin: eumelanin and pheomelanin, says Leann Poston, MD, a licensed physician. The wide diversity of possible hair colors comes from the production ratio of these two types of melanin.

Melanin is created from melanocytes, which are the cells found in your skin and hair follicles. When melanocytes stop producing melanin, your hair color changes to gray.

Melanocytes often stop producing melanin as you age, which is why gray hair is so common among the elderly. However, its common for hair to start turning gray around age 35.

Overall, Poston says that a combination of factors such as genetics, hormones, and your environment will determine exactly when your hair turns gray.

Though stress alone will not cause gray hair, there is some research that suggests it may speed up the graying process.

For example, a 2020 study published by the journal Nature found that when mice were exposed to stress, they lost melanocyte cells and gained gray hair as a result.

This is an interesting study that links stress to an abnormal conversion of stem cells to a more differentiated form, melanocytes, Poston says.

Melanocyte stem cells typically decrease in numbers as you age. But premature activation, associated with increases in a stress hormone called norepinephrine (or noradrenaline), actually caused these cells to decline more quickly in mice leading to the gray hair that researchers observed.

Poston says she doesnt believe this animal study is enough to definitively say that the same is true for humans. But other research has also suggested that stress can accelerate graying.

For example, a 2018 study in the International Journal of Trichology observed an increase in oxidative stress as a result of psychological stress and higher levels of oxidative stress, which contributes to a complicated biological imbalance in humans, are associated with an increased risk of many chronic diseases as well as premature aging.

The study suggests that premature gray hair, or the graying of hair by age 20, is linked with higher levels of oxidative stress, which may increase with more of your everyday psychological stressors like a difficult job or the pressure to provide for your family.

In addition, cigarette smoking and vitamin deficiencies which can also increase oxidative stress have been associated with early graying.

Overall, genetics and aging are likely to be more determinate for when your hair turns gray. But, as some research has suggested, psychological stress and other unhealthy risk factors may accelerate this graying process.

Read more:
Does stress cause gray hair? It may lead to premature graying - Business Insider

Skin Stem Cells Comments Off on Does stress cause gray hair? It may lead to premature graying – Business Insider | April 14th, 2020

More than 25 EINDs approved by FDA for leronlimab use in COVID-19 patients

Phase 2 trial - As of last week, 12 patients enrolled from 2 sites; 3 more sites to initiate enrollment this week, for a total of 5 sites

Phase 2b/3 trial - First hospital cleared to enroll patients beginning today

VANCOUVER, Washington, April 13, 2020 (GLOBE NEWSWIRE) -- CytoDyn Inc. (OTC.QB: CYDY), (CytoDyn or the Company), a late-stage biotechnology company developing leronlimab (PRO 140), a CCR5 antagonist with the potential for multiple therapeutic indications, announced today a comprehensive update and overview of the therapeutic indications from over 30 COVID-19 patients recently treated with leronlimab in over 4 hospitals and clinics throughout the country. More than 25 hospitals, to date, have requested participation in the Companys trials.

Patient enrollment in the Companys two clinical trials and Emergency Investigational New Drug (EIND) is as follows:

-- More than 25 patients have been administered leronlimab under EINDs authorized by the U.S. Food and Drug Administration (FDA). -- Rate of response in mild-to-moderate patients under EIND has been very promising with the first five patients treated being removed from oxygen. -- As of last week, 12 patients have been treated in the Phase 2 trial for mild-to-moderate COVID-19 indications and, because it is a double-blinded, placebo-controlled trial, results are not yet available. -- First site cleared to enroll patients in Phase 2b/3 beginning today.

Nader Pourhassan, Ph.D., President and Chief Executive Officer of CytoDyn said, We continue to coordinate around the clock with healthcare professionals across the country to deliver leronlimab to patients and we are in regular contact with the FDA to ensure they receive current patient data. We are planning to rapidly enroll 75 patients and report the results to the FDA as quickly as possible.

About Coronavirus Disease 2019SARS-CoV-2 was identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China. The origin of SARS-CoV-2 causing the COVID-19 disease is uncertain, and the virus is highly contagious. COVID-19 typically transmits person to person through respiratory droplets, commonly resulting from coughing, sneezing, and close personal contact. Coronaviruses are a large family of viruses, some causing illness in people and others that circulate among animals. For confirmed COVID-19 infections, symptoms have included fever, cough, and shortness of breath. The symptoms of COVID-19 may appear in as few as two days or as long as 14 days after exposure. Clinical manifestations in patients have ranged from non-existent to severe and fatal. At this time, there are minimal treatment options for COVID-19.

About Leronlimab (PRO 140) The FDA has granted a Fast Track designation to CytoDyn for two potential indications of leronlimab for deadly diseases. The first as a combination therapy with HAART for HIV-infected patients and the second is for metastatic triple-negative breast cancer. Leronlimab is an investigational humanized IgG4 mAb that blocks CCR5, a cellular receptor that is important in HIV infection, tumor metastases, and other diseases, including NASH. Leronlimab has completed nine clinical trials in over 800 people, including meeting its primary endpoints in a pivotal Phase 3 trial (leronlimab in combination with standard antiretroviral therapies in HIV-infected treatment-experienced patients).

In the setting of HIV/AIDS, leronlimab is a viral-entry inhibitor; it masks CCR5, thus protecting healthy T cells from viral infection by blocking the predominant HIV (R5) subtype from entering those cells. Leronlimab has been the subject of nine clinical trials, each of which demonstrated that leronlimab could significantly reduce or control HIV viral load in humans. The leronlimab antibody appears to be a powerful antiviral agent leading to potentially fewer side effects and less frequent dosing requirements compared with daily drug therapies currently in use.

In the setting of cancer, research has shown that CCR5 may play a role in tumor invasion, metastases, and tumor microenvironment control. Increased CCR5 expression is an indicator of disease status in several cancers. Published studies have shown that blocking CCR5 can reduce tumor metastases in laboratory and animal models of aggressive breast and prostate cancer. Leronlimab reduced human breast cancer metastasis by more than 98% in a murine xenograft model. CytoDyn is, therefore, conducting a Phase 1b/2 human clinical trial in metastatic triple-negative breast cancer and was granted Fast Track designation in May 2019.

The CCR5 receptor appears to play a central role in modulating immune cell trafficking to sites of inflammation. It may be crucial in the development of acute graft-versus-host disease (GvHD) and other inflammatory conditions. Clinical studies by others further support the concept that blocking CCR5 using a chemical inhibitor can reduce the clinical impact of acute GvHD without significantly affecting the engraftment of transplanted bone marrow stem cells. CytoDyn is currently conducting a Phase 2 clinical study with leronlimab to support further the concept that the CCR5 receptor on engrafted cells is critical for the development of acute GvHD, blocking the CCR5 receptor from recognizing specific immune signaling molecules is a viable approach to mitigating acute GvHD. The FDA has granted orphan drug designation to leronlimab for the prevention of GvHD.

About CytoDyn CytoDyn is a late-stage biotechnology company developing innovative treatments for multiple therapeutic indications based on leronlimab, a novel humanized monoclonal antibody targeting the CCR5 receptor. CCR5 appears to play a critical role in the ability of HIV to enter and infect healthy T-cells. The CCR5 receptor also appears to be implicated in tumor metastasis and immune-mediated illnesses, such as GvHD and NASH. CytoDyn has successfully completed a Phase 3 pivotal trial with leronlimab in combination with standard antiretroviral therapies in HIV-infected treatment-experienced patients. CytoDyn plans to seek FDA approval for leronlimab in combination therapy and plans to complete the filing of a Biologics License Application (BLA) in April of 2020 for that indication. CytoDyn is also conducting a Phase 3 investigative trial with leronlimab as a once-weekly monotherapy for HIV-infected patients. CytoDyn plans to initiate a registration-directed study of leronlimab monotherapy indication. If successful, it could support a label extension. Clinical results to date from multiple trials have shown that leronlimab can significantly reduce viral burden in people infected with HIV with no reported drug-related serious adverse events (SAEs). Moreover, a Phase 2b clinical trial demonstrated that leronlimab monotherapy can prevent viral escape in HIV-infected patients; some patients on leronlimab monotherapy have remained virally suppressed for more than five years. CytoDyn is also conducting a Phase 2 trial to evaluate leronlimab for the prevention of GvHD and a Phase 1b/2 clinical trial with leronlimab in metastatic triple-negative breast cancer. More information is at http://www.cytodyn.com.

Forward-Looking Statements This press release contains certain forward-looking statements that involve risks, uncertainties and assumptions that are difficult to predict. Words and expressions reflecting optimism, satisfaction or disappointment with current prospects, as well as words such as believes, hopes, intends, estimates, expects, projects, plans, anticipates and variations thereof, or the use of future tense, identify forward-looking statements, but their absence does not mean that a statement is not forward-looking. The Companys forward-looking statements are not guarantees of performance, and actual results could vary materially from those contained in or expressed by such statements due to risks and uncertainties including: (i) the sufficiency of the Companys cash position, (ii) the Companys ability to raise additional capital to fund its operations, (iii) the Companys ability to meet its debt obligations, if any, (iv) the Companys ability to enter into partnership or licensing arrangements with third parties, (v) the Companys ability to identify patients to enroll in its clinical trials in a timely fashion, (vi) the Companys ability to achieve approval of a marketable product, (vii) the design, implementation and conduct of the Companys clinical trials, (viii) the results of the Companys clinical trials, including the possibility of unfavorable clinical trial results, (ix) the market for, and marketability of, any product that is approved, (x) the existence or development of vaccines, drugs, or other treatments that are viewed by medical professionals or patients as superior to the Companys products, (xi) regulatory initiatives, compliance with governmental regulations and the regulatory approval process, (xii) general economic and business conditions, (xiii) changes in foreign, political, and social conditions, and (xiv) various other matters, many of which are beyond the Companys control. The Company urges investors to consider specifically the various risk factors identified in its most recent Form 10-K, and any risk factors or cautionary statements included in any subsequent Form 10-Q or Form 8-K, filed with the Securities and Exchange Commission. Except as required by law, the Company does not undertake any responsibility to update any forward-looking statements to take into account events or circumstances that occur after the date of this press release.

CYTODYN CONTACTSInvestors: Dave Gentry, CEO RedChip Companies Office: 1.800.RED.CHIP (733.2447) Cell: 407.491.4498 dave@redchip.com

Continued here:
Southern California Patients Treated with Leronlimab for COVID-19 under Emergency IND: 4 Patients with Moderate Indications Removed from Oxygen; 3...

Bone Marrow Stem Cells Comments Off on Southern California Patients Treated with Leronlimab for COVID-19 under Emergency IND: 4 Patients with Moderate Indications Removed from Oxygen; 3… | April 13th, 2020

SUZHOU, Chinaand SHANGHAI, April 13, 2020 /PRNewswire/ -- Gracell Biotechnologies Co., Ltd. ("Gracell"), a clinical-stage immune cell and gene therapy company, is pleased to announce that their first-in-human phase I data of Universal TruUCAR GC027 in relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia (T-ALL) was accepted for plenary oral presentation at the America Association for Cancer Research (AACR) Annual Meeting.

Gracell Logo (PRNewsfoto/Gracell)

This year's AACR presentations are moved to be held virtually to allow sharing the data in a timely fashion. A series of online sessions featuring presentations will be provided. Gracell will report the clinical safety and efficacy of GC027, an off-the-shelf CAR-T product based on Gracell's TruUCAR technology, for treatment of adult T-ALL patients.

"We are very pleased that AACR has accepted the phase I results of GC027, a first-in-human off-the-shelf TruUCAR product for plenary oral presentation. Gracell's proprietary TruUCAR platform was protected with patents of novel designs and unique features. Remarkably, GC027 derived from HLA unmatched donor's cells, is a monotherapy without co-administration of other immunosuppressive drug." said Dr. William CAO, founder and CEO of Gracell. "We are pleased to share thefirst-in-human phase I data with the scientific community."

Presentation: Safety and efficacy clinical study of TruUCART GC027: the first-in-human, universal CAR-T therapy for relapsed/refractory T-cell acute lymphoblastic leukemiaAbstract #9564Online live section: Apr. 27-28, EDT

About GC027GC027 was manufactured fromT cells of human leukocyte antigen (HLA) unmatched healthy donors using TruUCAR technology. TruUCAR allows the allogeneic CAR-T cells to proliferate and persist in HLA-unmatched patients (recipients) with minimized risk of graft-versus-host-disease (GvHD). GC027 is currently being developed as an investigational, off-the-shelf CAR-T cell therapy for treatment of T cell malignancies. The use of HLA unmatched healthy donor's cells may improve efficacy and reduce production time, available for off-the-shelf use in a timely manner.

About TruUCARTruUCAR is Gracell's proprietary and patented platform technology, with selected genes being edited to avoid GvHD and immune rejection without using strong immunosuppressive drugs. In addition to T-ALL antigen, the platform technology can also be implemented for other targets of hematological malignancies.

About T-ALLT - Lymphoblastic Leukemia (T-ALL) is an aggressive form of acute lymphoblastic leukemia, with a diffuse invasion of bone marrow and peripheral blood. In 2015, T-ALL affected around 876,000 people globally and resulted in 110,000 deaths worldwide. T-ALL compromises about 15%-20% of all children and adult acute lymphoblastic leukemia[1].Current standard of care therapies for T-ALL are chemotherapy and stem cell transplantation. 40-50% of patients will experience relapse within two years following front line therapy with limited treatment options available[2] [3]. Treatment of relapsed and refractory T-ALL remains a high unmet medical need.

About GracellGracell Biotechnologies Co., Ltd. ("Gracell") is a clinical-stage biotech company, committed to developing highly reliable and affordable cell gene therapies for cancer. Gracell is dedicated to resolving the remaining challenges in CAR-T, such as high production costs, lengthy manufacturing process, lack of off-the-shelf products, and inefficacy against solid tumors. Led by a group of world-class scientists, Gracell is advancing FasTCAR, TruUCAR (off-the-shelf CAR), Dual CAR and Enhanced CAR-T cell therapies for leukemia, lymphoma, myeloma, and solid tumors.

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Gracell to Present the First-in-human, Universal TruUCAR GC027 Therapy for Relapsed or Refractory T-cell Acute Lymphoblastic Leukemia at the AACR...

Bone Marrow Stem Cells Comments Off on Gracell to Present the First-in-human, Universal TruUCAR GC027 Therapy for Relapsed or Refractory T-cell Acute Lymphoblastic Leukemia at the AACR… | April 13th, 2020

Stress can affect the body in many different ways. And while it seems that stressful life events like being president may cause gray hair, the truth is a bit more complicated.

Gray hair is likely caused by a combination of genetics, aging, and hormones, and there is some research to suggest that stress can turn hair gray prematurely. Here's what you need to know.

When you're born, your hair color is determined by natural pigments in your skin called melanin.

"Human hair follicles contain two types of melanin: eumelanin and pheomelanin," says Leann Poston, MD, a licensed physician. "The wide diversity of possible hair colors comes from the production ratio of these two types of melanin."

Melanin is created from melanocytes, which are the cells found in your skin and hair follicles. When melanocytes stop producing melanin, your hair color changes to gray.

Melanocytes often stop producing melanin as you age, which is why gray hair is so common among the elderly. However, it's common for hair to start turning gray around age 35.

Overall, Poston says that a combination of factors such as genetics, hormones, and your environment will determine exactly when your hair turns gray.

Though stress alone will not cause gray hair, there is some research that suggests it may speed up the graying process.

For example, a 2020 study published by the journal Nature found that when mice were exposed to stress, they lost melanocyte cells and gained gray hair as a result.

"This is an interesting study that links stress to an abnormal conversion of stem cells to a more differentiated form, melanocytes," Poston says.

Melanocyte stem cells typically decrease in numbers as you age. But premature activation, associated with increases in a stress hormone called norepinephrine (or noradrenaline), actually caused these cells to decline more quickly in mice leading to the gray hair that researchers observed.

Poston says she doesn't believe this animal study is enough to definitively say that the same is true for humans. But other research has also suggested that stress can accelerate graying.

For example, a 2018 study in the International Journal of Trichology observed an increase in oxidative stress as a result of psychological stress and higher levels of oxidative stress, which contributes to a complicated biological imbalance in humans, are associated with an increased risk of many chronic diseases as well as premature aging.

The study suggests that premature gray hair, or the graying of hair by age 20, is linked with higher levels of oxidative stress, which may increase with more of your everyday psychological stressors like a difficult job or the pressure to provide for your family.

In addition, cigarette smoking and vitamin deficiencies which can also increase oxidative stress have been associated with early graying.

Overall, genetics and aging are likely to be more determinate for when your hair turns gray. But, as some research has suggested, psychological stress and other unhealthy risk factors may accelerate this graying process.

View original post here:
Does stress cause gray hair? It may lead to premature graying - Insider - INSIDER

Skin Stem Cells Comments Off on Does stress cause gray hair? It may lead to premature graying – Insider – INSIDER | April 13th, 2020

Theres no doubt that as we get older, our skin's wants and needs begin to change. Whileskincare routines of our late teens andearly twenties might have focused heavily on oil-absorbing products that worked to keepbreakouts in check, as we enter our thirties, its likely that other, more pressingskin issues start cropping up. For instance, spots of pigmentation might start surfacing, fine lines may begin to form and skin that was once plump andglowing could appear lacklustre and dull.

The sorry truth is that as we enter our thirties, all of the stuff that makes our skin naturally healthy starts to deteriorate. By the time we get to our thirties, we have around 50% collagen left in our skin.Hyaluronic acid production also slows down and cellular turnover only hits us around every four to six weeks. Everything starts to slow down, says celebrity facialist, Michaella Bolder.

So what exactly does all of this mean? And how can we help minimise the affects of ageing on our skin? To help decode everything there is to know about caring for skin in your thirties, I caught up with some of the top skincare experts in the business. Unsurprisingly, I found that, for the most part, they all preached the same message: As we make our way into our thirties, certainingredients simply cannot be compromised on.

Keeping scrolling for the six products they seriously recommend and to shop the best formulas out there.

As we enter our thirties, its understandable to assume that well start experiencing less breakouts as natural oil production starts to decline. However, thats not to say that regularexfoliation isnt necessary anymore.

Just because breakouts are most associated with teenage years, acne can still occur well into our thirties. In my clinical practice I frequently see patients in their thirties with adult onset acne, says Dr Catherine Borysiewicz, Consultant Dermatologist at the Cadogan Clinic. Data suggests women are more frequently affected by adult acne compared with men. The exact reason for this is unknown, but felt to be related to fluctuating hormone levels: during periods or from birth control pills, and also during and following pregnancy. The role of stress is also becoming more apparent, she warns.

Not only do regular acid treatments encourage cell turnover (something that starts slowing down in our thirties), they can also help to exfoliate for a clearer, more radiant complexion. Just remember, only exfoliate once or twice a week and always follow up with SPF.

REN Clean Skincare Ready Steady Glow Daily AHA Tonic (27)

Medik8 Blemish Control Pads (26)

Paula's Choice Resist Advanced Smoothing Treatment 10% AHA (37)

This Works Morning Expert Multi-Acid Pads (33)

Weve heard it time and time again, but its true that no skincare routine is complete without some sort ofvitamin C product, especially if youre in your thirties. But what exactly is it, and what does it do? To start with, vitamin C is a very powerful antioxidant that works against skin-damaging free radicals such as pollution and UV. And unfortunately, by the time we reach our thirties, the effects of free radical damage start to become more and more evident. Vitamin C eradicates free radicals that have hidden within our skin cells that start to diminish our healthy cells, turning them into unhealthy, broken ones. It basically eats free radicals up like Pacman, says Bolder.

On top of that, vitamin C is great for treating pigmentation and lightening dark spots without altering normal skin tone. Leading aesthetic doctor and surgeon,Dr Mayoni also warns, In our thirties, pigment cells can start to become overactive and so the skin starts to look less plump, less hydrated and with more areas of pigmentation appearing.

Drunk Elephant C-Firma Day Serum (67)

Kiehl's Powerful-Strength Line-Reducing Concentrate (52)

La Roche-Posay Pure Vitamin C10 Serum (38)

SkinCeuticals C E Ferulic Serum (140)

As a rule, it tends to be that the older we get, the more potent and active our skincare needs to be. However, there is one particular product that we can never have too much of. Although it sounds scary, hyaluronic acid isnt actually an acid in the way that you might think. Whereas most acids work to exfoliate, hyaluronic acid is a powerful moisture-binder that occurs naturally in our skin.

What is a moisture-binder, I hear you ask? Able to retain up to x1000 its own weight in water, hyaluronic acid is able to hold onto any moisture and hydration in order to keep skin looking plump and supple. The bad news is that as we enter our thirties, our hyaluronic acid supplies start declining. Upon reaching our thirties, our natural stores of hyaluronic acid decrease, warns Rowan Hall-Farrise, Head of Global Education at QMS Medicosmetics. Not only does the amount that our skin naturally produces start to diminish, but years of exposure to free radicals also begins to wear our existing supplies down, hence why vitamin C is important. Are you keeping up?

Using a hyaluronic acid serum twice a day is essential and be sure to apply it 10 minutes before you use any retinol, advises Bolder.

Zelens Z Hyaluron Hyaluronic Acid Complex Serum Drops (55)

The INKEY List Hyaluronic Acid Serum (6)

Vichy Mineral 89 (25)

Eucerin Hyaluron-Filler Ultra Light Moisture Booster Gel-Cream (25)

Collagen might just be one of the most-mentioned words in beauty advertising, but its actually quite a complex thing. A naturally-occurring protein, collagen is the stuff that really helps hold everything together and support the skin, making it healthy, plump and bouncy. Just like hyaluronic acid, free radicals and ageing start to impact our collagen production as we get into our thirties. From the age of 25, our collagen production starts to decrease. Our late twenties and early thirties is when we should start incorporating collagen treatments into our regimens, says Hall-Farrise.

However, despite what beauty brands might tell you, supplementing collagen isn't as easy as slapping on a collagen-infused face cream - the molecules are far too big to be absorbed by the skin. Luckily, there are ways to encourage the bodys natural collagen production, but were warning you that they dont come cheap. The professional treatment of microneedling helps to stimulate collagen, but you can also use stem cell products at home. The stem cells are there to encourage collagen stimulation and preserve the collagen that we have left in our skin, says Bolder.

If you can't justify the expense, don't worry too much, keeping on top of your hyaluronic acid serums twice a day should be enough to keep skin looking plump and firm in the short term.

Augustinus Bader The Cream (205)

QMS Medicosmetics Collagen System Sensitive (199)

Sarah Chapman Skinesis Stem Cell Collagen Activator Duo (149)

Indie Lee Stem Cell Serum (127)

You knew this was coming, right? While its all too easy to switch off the minute you hear the word retinol (seriously, do we ever stop talking about it?), experts warn that now is actually the time to start paying attention. In fact, Bolder actually advises against using retinol any time before your mid-thirties. Retinol should not be in your early thirties, but in your mid to late thirties I recommend starting to use a retinol at around 1%, she says.

If youre totally out of the loop with exactly what retinol does and why its beautys ingredient du jour, let me explain. A form of vitamin A (dont be fooled by the word vitamin, this stuff is seriously powerful), retinol increases cell turnover and is thought to be one of the only skincare ingredients that can actually help reverse the signs of ageing. Dr Laura Hamilton, aesthetic doctor and founder ofVictor & Garth explains, Retinol can really do wonders for your skin. It can improve skin texture, reduce pore size and minimise the appearance of fine lines and wrinkles. In our thirties, most of us will see results with retinol.

But be warned, its not always fun and games. Side effects of redness and peeling can take some getting used to, so start with a lower strength twice a week at night time only and build up, says Dr Hamilton.

La Roche-Posay Retinol B3 Serum (39)

Sunday Riley A+ High-Dose Retinoid Serum (70)

Origins Plantscription Overnight Moisturiser (49)

Elizabeth Arden Retinol Ceramide Line Erasing Night Serum Capsules X 30 (38)

Sure, the importance of SPF application might not be specific to any one decade of your life, but its crucial to reiterate that it should always feature in your daily skincare routine if you want to protect your skin from sun damage and ageing. While daily sun cream application might have been considered a more preventative measure in your twenties, in your thirties you might be starting to notice the physical damage that prolonged sun exposure can cause. Sun damage starts to come through in your thirties. So while vitamin C and retinol are needed to help reduce the damage already caused, SPF every single day will help prevent any further sun damage, says Bolder.

The Body Shop Skin Defence Multi-Protection Lotion SPF 50+ (18)

Institut Esthederm Adaptasun Sensitive Skin Face Cream Strong Sun (30)

Medik8 Advanced Day Total Protect (55)

Shiseido Expert Sun Ageing Protection Lotion SPF30 (35)

Next up, I've done my research, and these are the best anti-ageing products.

This article originally appeared on Who What Wear

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The 6 Skin Products Experts Say Every 30-Something Should Have in Their Routine - Yahoo Style

Skin Stem Cells Comments Off on The 6 Skin Products Experts Say Every 30-Something Should Have in Their Routine – Yahoo Style | April 13th, 2020

Coronavirus (Image source: U.S. Department of State)

In my February column, I wrote about the fact that I had a stem cell transplant in early December 2019, about a month before I heard for the first time about the coronavirus.

The transplant entailed getting an unrelated donors stem cells to replace mine; then, if all went according to plan, these cells would grow into a new immune system to seek and destroy my cancer cells.

As a result of the transplant, all of my childhood vaccinations became ineffective. I was instructed to stay in isolation for at least four months in order to avoid infectious and possibly deadly diseases like influenza. Consequently, I have been quarantined since December.

Just a day before writing this, a friend told me that Im a trendsetter.

I knew very little about viruses before the coronavirus came alongonly that they were microscopic infectious organisms that invade living cells and then reproduce. In an effort to review what I had been (mostly unconsciously) protected from before transplant, I Googled the Centers for Disease Control and Prevention (CDC) and found a piece entitled, Vaccines for children: Diseases you almost forgot about.

I was reminded that most of us had vaccines as children for some of the nastiest viruses, including polio, which invades the brain and spinal cord and leads to paralysis; tetanus, a potentially fatal disease that causes lockjaw; whooping cough, which can lead to violent coughing that makes it difficult to breathe; and many more.

Most older adults are familiar with chicken pox, mumps and measles. I had two of them as a young teenager. One that I forgot about is diphtheria, which affects breathing or swallowing and can lead to heart failure, paralysis and death. There are several more.

I imagined the panic that parents must have felt and the pain that young children must have experienced before vaccines were discovered to prevent these horrible infectious diseases.

For the time being, I cannot replace my old vaccines. I must wait for at least one year while my new immune system gets stronger.

The idea of being in isolation and maintaining a safe social distance for a few months post-transplant made sense to me. I was well prepared by doctors and nurses and I knew my wife would be a great caregiver, so I thought I could do the time.

And then, the coronavirus came along.

For me, being quarantined was an old hat by the time a national emergency was declared and everything started to shut down. I learned that this new virus main target was the lungs and people older than 60 years with underlying health conditions were its primary targets.

I fit the bill and knew that Id have to do more time: at least another three months, my transplant doctor told me. The only difference is that this time, hundreds of millions of people would be joining me.

I was well-prepared before and after my transplant. I knew why I had to self-isolate and for how long. No one, including me, was prepared for COVID-19 and the mass quarantine that it now requiresnot only to protect oneself and ones family, but also to protect strangers. Mostly older strangers like me.

Scientists and other health professionals were the heroes of viral epidemics gone by. I do believe we will get through this, with people like immunologist Dr. Anthony Fauci leading the way.

Still, the unknown is what is most frightening. We all want answers, yet some remain illusive at the moment. This is an opportunity for all of us to strengthen our tolerance for ambiguity.

When will this end? No clue. Will it come back? No idea.

Although my new immune system needs more time to protect me, I just found out after a PET scan that Im in complete remission from my cancer.

Will it come back? No idea.

We are all in the same boat, living in uncertainty, whether young or old, healthy or unwell. As Plato said, Be kind, for everyone you meet is fighting a harder battle.

Andrew Malekoff is the executive director of North Shore Child and Family Guidance Center. To find out more, call 516-626-1971 or visit http://www.northshorechildguidance.org.

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A Quarantine Trendsetter - Long Island Weekly News

Spinal Cord Stem Cells Comments Off on A Quarantine Trendsetter – Long Island Weekly News | April 13th, 2020